Associations between alcohol use and sex-specific maturation of subcortical gray matter morphometry from adolescence to adulthood: Replication across two longitudinal samples.

Subcortical brain morphometry matures across adolescence and young adulthood, a time when many youth engage in escalating levels of alcohol use. Initial cross-sectional studies have shown alcohol use is associated with altered subcortical morphometry. However, longitudinal evidence of sex-specific neuromaturation and associations with alcohol use remains limited. This project used generalized additive mixed models to examine sex-specific development of subcortical volumes and associations with recent alcohol use, using 7 longitudinal waves (n = 804, 51% female, ages 12-21 at baseline) from the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA). A second, independent, longitudinal dataset, with up to four waves of data (n = 467, 43% female, ages 10-18 at baseline), was used to assess replicability. Significant, replicable non-linear normative volumetric changes with age were evident in the caudate, putamen, thalamus, pallidum, amygdala and hippocampus. Significant, replicable negative associations between subcortical volume and alcohol use were found in the hippocampus in all youth, and the caudate and thalamus in female but not male youth, with significant interactions present in the caudate, thalamus and putamen. Findings suggest a structural vulnerability to alcohol use, or a predisposition to drink alcohol based on brain structure, with female youth potentially showing heightened risk, compared to male youth.

Circadian misalignment and weekend alcohol use in late adolescent drinkers: preliminary evidence.

Alcohol use accelerates during late adolescence, predicting the development of alcohol use disorders (AUDs) and other negative outcomes. Identifying modifiable risk factors for alcohol use during this time could lead to novel prevention approaches. Burgeoning evidence suggests that sleep and circadian factors are cross-sectionally and longitudinally linked to alcohol use and problems, but more proximal relationships have been understudied. Circadian misalignment, in particular, is hypothesized to increase the risk for AUDs, but almost no published studies have included a biological measure of misalignment. In the present study, we aimed to extend existing research by assessing the relationship between adolescent circadian misalignment and alcohol use on a proximal timeframe (over two weeks) and by including three complementary measures of circadian alignment. We studied 36 healthy late (18-22 years old, 22 females) alcohol drinkers (reporting ≥1, standard drink per week over the past 30 days) over 14 days. Throughout the study, participants reported prior day's alcohol use and prior night's sleep each morning via smartphone and a secure, browser-based interface. Circadian phase was assessed via the dim light melatonin onset (DLMO) in the laboratory on two occasions (Thursday and Sunday nights) in counterbalanced order. The three measures of circadian alignment included DLMO-midsleep interval, "classic" social jet lag (weekday-weekend difference in midsleep), and "objective" social jet lag (weekday-weekend difference in DLMO). Multivariate imputation by chained equations was used to impute missing data, and Poisson regression models were used to assess associations between circadian alignment variables and weekend alcohol use. Covariates included sex, age, Thursday alcohol use, and Thursday sleep characteristics. As predicted, greater misalignment was associated with greater weekend alcohol use for two of the three alignment measures (shorter DLMO-midsleep intervals and larger weekday-weekend differences in midsleep), while larger weekday-weekend differences in DLMO were associated with less alcohol use. Notably, in contrast to expectations, the distribution of weekday-weekend differences in DLMO was nearly equally distributed between individuals advancing over the weekend and those delaying over the weekend. This unexpected finding plausibly reflects the fact that college students are not subject to the same systematically earlier weekday schedules observed in high school students and working adults. These preliminary findings support the need for larger, more definitive studies investigating the proximal relationships between circadian alignment and alcohol use among late adolescents.

K-Complexes: Interaction between the Central and Autonomic Nervous Systems during Sleep.

STUDY OBJECTIVES: To investigate the relationship between K-complexes (KCs) and cardiac functioning. METHODS: Forty healthy adolescents aged 16-22 y (19 females) participated in the study. Heart rate (HR) fluctuations associated with spontaneous and evoked KCs were investigated on two nights, one with (event-related potential night) and one without auditory tones presented across the night. RESULTS: There was a clear biphasic cardiac response to evoked and spontaneous KCs, with an initial acceleration in HR followed by a deceleration (P < 0.001). HR acceleration occurred immediately to KCs in response to tones presented in the first third of the interbeat interval, but was delayed a beat when the tone occurred later in the cardiac cycle (P < 0.05). Sex differences were also evident. Pretone baseline HR was higher, and the magnitude of the HR response was blunted and delayed, in female compared to male adolescents (P < 0.001). Also, pretone baseline HR was lower when a tone elicited a KC compared to when it did not (P < 0.001), suggesting that KCs are possibly more likely to be elicited by external stimuli in states of reduced cardiac activation. CONCLUSIONS: The strict dependency observed between KCs and cardiac control indicates a potential role of KCs in modulating the cardiovascular system during sleep. Sex differences in the KC-cardiac response indicate the sensitivity of this measure in capturing sex differences in cardiac regulatory physiology.

Double-blind randomised controlled trial of vitamin D3 supplementation for the prevention of acute respiratory infection in older adults and their carers (ViDiFlu).

RATIONALE: Low-dose vitamin D supplementation is already recommended in older adults for prevention of fractures and falls, but clinical trials investigating whether higher doses could provide additional protection against acute respiratory infection (ARI) are lacking. OBJECTIVE: To conduct a clinical trial of high-dose versus low-dose vitamin D3 supplementation for ARI prevention in residents of sheltered-accommodation housing blocks ('schemes') and their carers in London, UK. MEASUREMENTS AND METHODS: Fifty-four schemes (137 individual participants) were allocated to the active intervention (vitamin D3 2.4 mg once every 2 months +10 µg daily for residents, 3 mg once every 2 months for carers), and 54 schemes with 103 participants were allocated to control (placebo once every 2 months +vitamin D3 10 µg daily for residents, placebo once every 2 months for carers) for 1 year. Primary outcome was time to first ARI; secondary outcomes included time to first upper/lower respiratory infection (URI/LRI, analysed separately), and symptom duration. MAIN RESULTS: Inadequate vitamin D status was common at baseline: 220/240 (92%) participants had serum 25(OH)D concentration <75 nmol/L. The active intervention did not influence time to first ARI (adjusted HR (aHR) 1.18, 95% CI 0.80 to 1.74, p=0.42). When URI and LRI were analysed separately, allocation to the active intervention was associated with increased risk of URI (aHR 1.48, 95% CI 1.02 to 2.16, p=0.039) and increased duration of URI symptoms (median 7.0 vs 5.0 days for active vs control, adjusted ratio of geometric means 1.34, 95% CI 1.09 to 1.65, p=0.005), but not with altered risk or duration of LRI. CONCLUSIONS: Addition of intermittent bolus-dose vitamin D3 supplementation to a daily low-dose regimen did not influence risk of ARI in older adults and their carers, but was associated with increased risk and duration of URI. TRIAL REGISTRATION NUMBER: clinicaltrials.gov NCT01069874.

Serotonin Transporter Genotype Linked to Adolescent Substance Use Treatment Outcome through Externalizing Behavior.

Meta-analyses suggest that the serotonin transporter linked polymorphic region (5-HTTLPR) short (S) allele, relative to the long (L) allele, is associated with risk for alcohol dependence, particularly among individuals with early onset antisocial alcoholism. Youth in substance use treatment tend to show antisocial or externalizing behaviors, such as conduct problems, which predict worse treatment outcome. This study examined a pathway in which 5-HTTLPR genotype is associated with externalizing behavior, and the intermediate phenotype of externalizing behavior serves as a link between 5-HTTLPR genotype and substance use treatment outcome in youth. Adolescents (n = 142) who were recruited from addictions treatment were genotyped for 5-HTTLPR polymorphisms (S and LG carriers vs. LALA), assessed for externalizing and internalizing behaviors shortly after starting treatment, and followed over 6-months. 5-HTTLPR genotype was not associated with internalizing behaviors, and was not directly associated with 6-month substance use outcomes. However, 5-HTTLPR genotype was associated with externalizing behaviors (S and LG > LALA), and externalizing behaviors predicted alcohol and marijuana problem severity at 6-month follow-up. Results indicated an indirect (p < 0.05) and non-specific (i.e., both alcohol and marijuana severity) effect of 5-HTTLPR genotype on youth substance use treatment outcomes, with externalizing behaviors as an important linking factor. Adolescents in substance use treatment with low expressing (S and LG) 5-HTTLPR alleles and externalizing behavior might benefit from intervention that addresses serotonergic functioning, externalizing behaviors, and substance use to improve outcomes.

White matter integrity as a link in the association between motivation to abstain and treatment outcome in adolescent substance users.

Readiness to change constitutes an important treatment target. This study examined white matter (WM) integrity as a possible link in the pathway between motivation to abstain and treatment outcome. Adolescents (age 14-18 years, n = 32) were recruited from intensive outpatient (IOP) substance use treatment and reported on motivation to abstain from alcohol and marijuana shortly after treatment admission (i.e., at baseline). Diffusion tensor imaging data were collected approximately 7 weeks after starting IOP and were used to quantify WM integrity (indexed by fractional anisotropy, FA) using a region of interest (ROI) approach. Treatment outcomes were assessed 6 months after baseline. Indirect effects analyses tested FA in prefrontal, orbitofrontal, and temporal ROIs as a linking variable in the pathway from motivation to abstain to alcohol and marijuana outcomes. Bivariate correlations indicated that greater motivation to abstain from alcohol was associated with lower FA in prefrontal, orbitofrontal, and temporal ROIs and that lower FA in these three ROIs was associated with greater 6-month alcohol problem severity. The indirect effect of FA was significant for the prefrontal ROI in the pathway from motivation to outcome for alcohol. FA values were not associated with motivation to abstain from marijuana or marijuana-related outcomes. Results suggest that lower WM integrity, particularly in the prefrontal brain region, may help to explain greater alcohol problem severity at 6 months despite higher motivation to abstain from alcohol. Interventions that aim to enhance WM integrity warrant attention to improve adolescent treatment outcomes.

Double-blind fluoxetine trial in comorbid MDD-CUD youth and young adults.

OBJECTIVE: This study compared the acute phase (12-week) efficacy of fluoxetine versus placebo for the treatment of the depressive symptoms and the cannabis use of adolescents and young adults with comorbid major depression (MDD) and a cannabis use disorder (CUD) (cannabis dependence or cannabis abuse). We hypothesized that fluoxetine would demonstrate efficacy versus placebo for the treatment of the depressive symptoms and the cannabis use of adolescents and young adults with comorbid MDD/CUD. METHODS: We conducted the first double-blind placebo-controlled study of fluoxetine in adolescents and young adults with comorbid MDD/CUD. All participants in both treatment groups also received manual-based cognitive behavioral therapy (CBT) and motivation enhancement therapy (MET) during the 12-week course of the study. RESULTS: Fluoxetine was well tolerated in this treatment population. No significant group-by-time interactions were noted for any depression-related or cannabis-use related outcome variable over the 12-week study. Subjects in both the fluoxetine group and the placebo group showed significant within-group improvement in depressive symptoms and in number of DSM diagnostic criteria for a CUD. Large magnitude decreases in depressive symptoms were noted in both treatment groups, and end-of-study levels of depressive symptoms were low in both treatment groups. CONCLUSIONS: Fluoxetine did not demonstrate greater efficacy than placebo for treating either the depressive symptoms or the cannabis-related symptoms of our study sample of comorbid adolescents and young adults. The lack of a significant between-group difference in these symptoms may reflect limited medication efficacy, or may result from efficacy of the CBT/MET psychotherapy or from limited sample size.

Cannabis withdrawal is common among treatment-seeking adolescents with cannabis dependence and major depression, and is associated with rapid relapse to dependence.

Recently, reports have suggested that cannabis withdrawal occurs commonly in adults with cannabis dependence, though it is unclear whether this extends to those with comorbid depression or to comorbid adolescents. We hypothesized that cannabis withdrawal would be common among our sample of comorbid adolescents and young adults, and that the presence of cannabis withdrawal symptoms would be associated with a self-reported past history of rapid reinstatement of cannabis dependence symptoms (rapid relapse). The participants in this study included 170 adolescents and young adults, including 104 with cannabis dependence, 32 with cannabis abuse, and 34 with cannabis use without dependence or abuse. All of these subjects demonstrated current depressive symptoms and cannabis use, and most demonstrated current DSM-IV major depressive disorder and current comorbid cannabis dependence. These subjects had presented for treatment for either of two double-blind, placebo-controlled trials involving fluoxetine. Cannabis withdrawal was the most commonly reported cannabis dependence criterion among the 104 subjects in our sample with cannabis dependence, being noted in 92% of subjects, using a two-symptom cutoff for determination of cannabis withdrawal. The most common withdrawal symptoms among those with cannabis dependence were craving (82%), irritability (76%), restlessness (58%), anxiety (55%), and depression (52%). Cannabis withdrawal symptoms (in the N=170 sample) were reported to have been associated with rapid reinstatement of cannabis dependence symptoms (rapid relapse). These findings suggest that cannabis withdrawal should be included as a diagnosis in the upcoming DSM-V, and should be listed in the upcoming criteria list for the DSM-V diagnostic category of cannabis dependence.

Prefrontal cortex, thalamus, and cerebellar volumes in adolescents and young adults with adolescent-onset alcohol use disorders and comorbid mental disorders.

BACKGROUND: In adults, prefrontal, thalamic, and cerebellar brain injury is associated with excessive ethanol intake. As these brain structures are actively maturing during adolescence, we hypothesized that subjects with adolescent-onset alcohol use disorders, compared with control subjects, would have smaller brain volumes in these areas. Thus, we compared prefrontal-thalamic-cerebellar measures of adolescents and young adults with adolescent-onset alcohol use disorders (AUD, defined as DSM-IV alcohol dependence or abuse) with those of sociodemographically similar control subjects. METHODS: Magnetic resonance imaging was used to measure prefrontal cortex, thalamic, and cerebellar volumes in 14 subjects (eight males, six females) with an AUD (mean age, 17.0+/-2.1 years) and 28 control subjects (16 males, 12 females; 16.9+/-2.3 years). All AUD subjects were recruited from substance abuse treatment programs and had comorbid mental disorders. RESULTS: Subjects with alcohol use disorders had smaller prefrontal cortex and prefrontal cortex white matter volumes compared with control subjects. Right, left, and total thalamic, pons/brainstem, right and left cerebellar hemispheric, total cerebellar, and cerebellar vermis volumes did not differ between groups. There was a significant sex-by-group effect, indicating that males with an adolescent-onset AUD compared with control males had smaller cerebellar volumes, whereas the two female groups did not differ in cerebellar volumes. Prefrontal cortex volume variables significantly correlated with measures of alcohol consumption. CONCLUSIONS: These findings suggest that a smaller prefrontal cortex is associated with early-onset drinking in individuals with comorbid mental disorders. Further studies are warranted to examine if a smaller prefrontal cortex represents a vulnerability to, or a consequence of, early-onset drinking.

Acute phase and five-year follow-up study of fluoxetine in adolescents with major depression and a comorbid substance use disorder: a review.

This paper reviews the results of an acute phase trial and a five-year follow-up study of fluoxetine in adolescents with major depression and a substance use disorder (SUD). This study included a 12-week open label acute phase study of 13 comorbid adolescents, followed by comprehensive assessments conducted 1, 3, and 5 years after entry into an acute phase fluoxetine trial. The results of the acute phase study and of the 1, 3, and 5-year follow-up assessments have already been published in four papers. The current paper was designed to cover the results of the study across the entire 5-year time spectrum of the study, and to summarize the clinical results across that entire time period. The data from this pilot study suggest that the long-term (5-year) clinical course for the Alcohol Dependence, Cannabis Dependence, and academic functioning of comorbid adolescents following acute phase treatment with SSRIs is generally good. However, the long-term clinical course for the Major Depression of that comorbid adolescent population is surprisingly poor.

Rapid relapse generally follows treatment for substance use disorders among adolescents.

This prospective study involved 59 adolescents with drug and alcohol disorders who had just completed outpatient treatment. They participated in a comprehensive baseline assessment, and then participated in monthly telephone assessments of substance use and reasons for use. Despite their recent treatment, two-thirds (66%) of the participants in this study had relapsed to drug use within 6 months. The median time to drug relapse was only 54 days (+/-14 days), or slightly less than 2 months. The three most commonly given reasons for relapse were social pressure, withdrawal, and negative affect. These findings provide a first confirmation of the results of S.A. Brown [Recovery patterns in adolescent substance abuse. (1993). In J. S. Baer, G. A. Marlatt, & R. J. McMahon (Eds.), Addictive behaviors across the life span (pp. 160-183). London: SAGE.] in showing that most adolescents relapse quickly following treatment for substance use disorders.