Faculty Bibliography

AIM: To investigate the efficacy of maintenance treatment with bupropion and/or nicotine gum for reducing smoking relapse. DESIGN, SETTING AND PARTICIPANTS: A 48-week study was conducted at a university-based smoking cessation clinic between February 2001 and October 2005. A total of 588 smokers received bupropion and nicotine patch in 8 weeks of open-label treatment (OLT); 289 abstainers during the last 4 weeks of OLT were randomized in double-blind placebo-controlled fashion to one of four arms for 16 weeks of maintenance treatment (MT) followed by 24 weeks of non-treatment follow-up (NTFU). INTERVENTION: Bupropion (300 mg/day) and 2 mg nicotine gum, used alone or combined, and comparable placebo pill and placebo gum. Behavioral counseling at all visits. OUTCOME: Time to relapse (TTR) from randomization. Relapse is defined as the first 7 consecutive days of smoking. Abstinence verified by carbon monoxide <or= 8 parts per million. FINDINGS: TTR was longer with extended active treatments compared to placebo (median days to relapse: bupropion + placebo = 136, nicotine + placebo = 98, bupropion + nicotine = 90, double placebo = 71). Hazard ratios (HR) for relapse were statistically significant for bupropion + placebo versus double placebo during MT (HR = 0.59, 95% CI = 0.37-0.92) and to the end of NTFU (HR = 0.66, 95% CI = 0.42-0.96). However, bupropion's advantage dissipated upon stopping the drug. Gum use was low, preventing a valid assessment; but analysis restricted to gum users suggested a weak effect of extended nicotine gum. CONCLUSION: Maintenance treatment with bupropion exerted a modest benefit for preventing smoking relapse; the optimum duration of bupropion treatment was unclear. Further research is needed to ascertain the merits of extended use of nicotine gum, other nicotine replacement agents and other treatments known to aid smokers for preventing relapse once abstinence is achieved

Children in child welfare are especially likely to have unmet mental health needs. The role of family factors in children's use of mental health services was examined in a longitudinal sample of 1075 maltreated or at-risk children. Vulnerable family environment (poor family functioning, low social support, and caregiver psychological distress) is an important predictor of children's mental health needs. It also predicts them not having these needs met.

OBJECTIVE: Controversy exists regarding whether nonepisodic irritability and hyperarousal (severe mood dysregulation) is a phenotype of pediatric bipolar disorder. The authors compared axis I diagnoses in parents of children with narrow phenotype bipolar disorder and parents of youth with severe mood dysregulation. METHOD: Parents of youth with narrow phenotype bipolar disorder (proband N=33, parent N=42) and youth with severe mood dysregulation (proband N=30, parent N=37) were interviewed by clinicians who were blind to the child's diagnostic status using the Diagnostic Interview for Genetic Studies. RESULTS: Compared to parents of youth with severe mood dysregulation, parents of youth with narrow phenotype bipolar disorder were significantly more likely to be diagnosed with bipolar disorder. There were no other diagnostic differences between the two groups. CONCLUSIONS: These data suggest that narrow phenotype bipolar disorder may be distinct from severe mood dysregulation in terms of familial aggregation. Additionally, the familiality of narrow phenotype bipolar disorder and adult DSM-IV bipolar disorder is high.

OBJECTIVE: The objectives of this pilot study were to explore the changes in symptom severity, tolerability, and the pharmacodynamics of venlafaxine treatment in youths with attention-deficit/hyperactivity disorder (ADHD). METHODS: This was a 2-week, open-label, outpatient trial of venlafaxine in children and adolescents, ages 5-17 years, with ADHD. Three dosing strata, 0.5, 1.0, and 2.0 mg/kg per day, were examined. ADHD symptom severity and improvement assessments included the ADHD Rating Scale (ARS-IV) and the Clinical Global Impressions Scale (CGI). During this study, venlafaxine, O-desmethylvenlafaxine (ODV), norepinephrine, and serotonin concentrations were obtained. RESULTS: Thirty-eight participants (33 males) were treated in this trial. Overall, parent-completed and teacher-completed ARS-IV total scores showed a statistically significant positive change at the end of the study when compared to baseline (p < 0.05). Significant increases in plasma venlafaxine concentrations were observed at day 15 when compared to day 8 (p = 0.04). In addition, plasma norepinephrine and serotonin concentrations were found to be significantly decreased from baseline at end of study (p < 0.05). Four patients ended participation in the study prematurely: lost to follow up (n = 2), withdrawal of consent (n = 1), and worsening of ADHD symptoms after 8 days of treatment (n = 1). There were no discontinuations due to other adverse events. CONCLUSIONS: Venlafaxine appeared to offer some benefit and appears to be relatively safe for the short-term treatment of ADHD in this open-label trial. The pharmacodynamics of venlafaxine in youths are consistent with serotonergic and neuradrenergic modulation

Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, plays an important role in synaptic plasticity. In this issue of Molecular Pharmacology, Ou and Gean (p. 350) thoroughly describe the molecular cascade by which fear learning leads to an increase in BDNF expression in the lateral amygdala (LA). Calcium influx through N-methyl-D-aspartate receptors and L-type voltage-dependent calcium channels, which occurs in the LA during fear conditioning, activates protein kinase A and Ca2+/calmodulin-dependent protein kinase IV. Each induces phosphorylation of cAMP response element-binding protein, which binds to the BDNF promoter, leading to BDNF expression in the LA, and contributes to fear memory consolidation

CONTEXT: Attention-deficit/hyperactivity disorder (ADHD) is the most prevalent psychiatric disorder of childhood. There is considerable evidence that brain dopamine is involved in ADHD, but it is unclear whether dopamine activity is enhanced or depressed. OBJECTIVE: To test the hypotheses that striatal dopamine activity is depressed in ADHD and that this contributes to symptoms of inattention. DESIGN: Clinical (ADHD adult) and comparison (healthy control) subjects were scanned with positron emission tomography and raclopride labeled with carbon 11 (D2/D3 receptor radioligand sensitive to competition with endogenous dopamine) after placebo and after intravenous methylphenidate hydrochloride (stimulant that increases extracellular dopamine by blocking dopamine transporters). The difference in [11C]raclopride's specific binding between placebo and methylphenidate was used as marker of dopamine release. Symptoms were quantified using the Conners Adult ADHD Rating Scales. SETTING: Outpatient setting. PARTICIPANTS: Nineteen adults with ADHD who had never received medication and 24 healthy controls. RESULTS: With the placebo, D2/D3 receptor availability in left caudate was lower (P < .05) in subjects with ADHD than in controls. Methylphenidate induced smaller decrements in [11C]raclopride binding in left and right caudate (blunted DA increases) (P < .05) and higher scores on self-reports of 'drug liking' in ADHD than in control subjects. The blunted response to methylphenidate in caudate was associated with symptoms of inattention (P < .05) and with higher self-reports of drug liking (P < .01). Exploratory analysis using statistical parametric mapping revealed that methylphenidate also decreased [11C]raclopride binding in hippocampus and amygdala and that these decrements were smaller in subjects with ADHD (P < .001). CONCLUSIONS: This study reveals depressed dopamine activity in caudate and preliminary evidence in limbic regions in adults with ADHD that was associated with inattention and with enhanced reinforcing responses to intravenous methylphenidate. This suggests that dopamine dysfunction is involved with symptoms of inattention but may also contribute to substance abuse comorbidity in ADHD

The ADOS characterizes socio-communicative deficits in autism spectrum disorders (ASD). In this study the effect of module choice on ADOS classification was examined. For 74 participants (52 autism, 22 PDD-NOS), Module 1 and Module 2 were administered in a single session. Fifty-one participants maintained ADOS classification, with 17 more impaired on M2 and 6 more impaired on M1. For 64 participants (25 autism, 39 PDD-NOS), Module 2 and Module 3 were administered. Thirty-nine participants maintained classification, with 24 more impaired on M3 and 1 more impaired on M2. As expected, more impairment was indicated when a module with more language and task demands was administered. Clinical judgment of the most appropriate module for administration was found to be important

Verbal skills were assessed at approximately ages 2, 3, 5, and 9 years for 206 children with a clinical diagnosis of autism (n = 98), pervasive developmental disorders-not otherwise specified (PDD-NOS; n = 58), or nonspectrum developmental disabilities (n = 50). Growth curve analyses were used to analyze verbal skills trajectories over time. Nonverbal IQ and joint attention emerged as strong positive predictors of verbal outcome. The gap between the autism and other 2 groups widened with time as the latter improved at a higher rate. However, there was considerable variability within diagnostic groups. Children with autism most at risk for more serious language impairments later in life can be identified with considerable accuracy at a very young age, while improvement can range from minimal to dramatic