Childhood Air Pollution Exposure Associated with Self-Reported Bronchitic Symptoms in Adulthood.

RATIONALE: Few studies have examined the effects of long-term childhood air pollution exposure on adult respiratory health, including whether childhood respiratory effects underlie this relation. OBJECTIVES: To evaluate associations between childhood air pollution exposure and self-reported adult bronchitic symptoms, while considering child respiratory health, in the Southern California Children's Health Study. METHODS: Nitrogen dioxide (NO2), ozone, particulate matter<2.5µm (PM2.5) and <10µm (PM10) exposures assessed using inverse-distance-squared spatial interpolation based on childhood (birth-17 years) residential histories. Bronchitic symptoms (bronchitis, cough, or phlegm in last 12 months) were ascertained via questionnaire in adulthood. Associations between mean air pollution exposure across childhood and self-reported adult bronchitic symptoms were estimated using logistic regression. We further adjusted for childhood bronchitic symptoms and asthma to understand whether associations operated beyond childhood respiratory health impacts. Effect modification was assessed for family history of asthma, childhood asthma, and adult allergies. MEASUREMENTS AND MAIN RESULTS: 1308 participants were included (mostly non-Hispanic White [56%] or Hispanic [32%]). At adult assessment (age mean=32.0 years, standard deviation [SD]=4.7) 25% reported bronchitic symptoms. Adult bronchitic symptoms were associated with NO2 and PM10 childhood exposures. Odds ratios per SD increase: 1.69 (95%CI:1.14,2.49) for NO2 (SD=11.1ppb); 1.51 (95%CI:1.00,2.27) for PM10 (SD=14.2µg/m3). Adjusting for childhood bronchitic symptoms or asthma produced similar results. NO2 and PM10 associations were modified by childhood asthma, with larger associations among asthmatics. CONCLUSION: Childhood NO2 and PM10 exposures were associated with adult bronchitic symptoms. Associations were not explained by childhood respiratory health impacts; however, participants with childhood asthma had stronger associations.

N-acetyl cysteine (NAC) augmentation in the treatment of obsessive-compulsive disorder: A phase III, 20-week, double-blind, randomized, placebo-controlled trial.

OBJECTIVE: Preliminary evidence has suggested that adjunctive N-acetylcysteine (NAC), an antioxidant precursor to glutathione, may reduce symptoms of obsessive-compulsive disorder (OCD). We conducted a 20-week, multi-site, randomized controlled trial to investigate the safety and efficacy of the adjunctive use of NAC in OCD. METHODS: The study was a phase III, 20-week, double-blind, randomized controlled trial across multiple sites in Australia investigating 2 g to 4 g per day of NAC (titrated according to response) in 98 participants with DSM-5 diagnosed OCD. Data were analysed using linear mixed effects models for the 89 participants who attended at least one follow-up visit. RESULTS: A modified intention-to-treat analysis of the primary outcome found no evidence that NAC reduced symptoms of OCD measured on the Yale-Brown Obsessive-Compulsive Scale, relative to placebo (mean difference at week 20 = 0.53, 95% compatibility interval = -2.18, 3.23; p = 0.70; favouring placebo). There was also no evidence that NAC, compared to placebo, improved outcomes on the secondary measures including anxiety, depression, quality of life, functioning, or clinician/participant impression. NAC was well-tolerated with only mild gastrointestinal adverse events associated with the treatment. CONCLUSION: We found no evidence supporting the efficacy of the adjunctive use of NAC in OCD.

The Impact of Race on Perioperative and Patient-Reported Outcomes following Autologous Breast Reconstruction.

BACKGROUND: Racial disparities are evident in multiple aspects of the perioperative care of breast cancer patients, but data examining whether such differences translate to clinical and patient-reported outcomes are limited. This study examined the impact of race on perioperative outcomes in autologous breast reconstruction. METHODS: A retrospective cohort study including all breast cancer patients who underwent immediate autologous breast reconstruction at a single institution from 2010 to 2017 was conducted. Self-reported race was used to classify patients into three groups: white, African American, and other. The primary and secondary endpoints were occurrence of any major complications within 30 days of surgery and patient-reported outcomes (measured with the BREAST-Q), respectively. Regression models were constructed to identify factors associated with the outcomes. RESULTS: Overall, 404 patients, including 259 white (64 percent), 63 African American (16 percent), and 82 patients from other minority groups (20 percent), were included. African American patients had a significantly higher proportion of preoperative comorbidities. Postoperatively, African American patients had a higher incidence of 30-day major complications (p = 0.004) and were more likely to return to the operating room (p = 0.006). Univariable analyses examining complications demonstrated that race was the only factor associated with 30-day major complications (p = 0.001). Patient-reported outcomes were not statistically different at each time point through 3 years postoperatively. CONCLUSIONS: African American patients continue to present with increased comorbidities and may be more likely to experience major complications following immediate autologous breast reconstruction. However, patient-reported satisfaction or physical well-being outcomes may not differ between groups. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.

Treatment of refractory obsessive-compulsive disorder with nutraceuticals (TRON): a 20-week, open label pilot study.

BACKGROUND: Obsessive-compulsive disorder (OCD) is often challenging to treat and resistant to psychological interventions and prescribed medications. The adjunctive use of nutraceuticals with potential neuromodulatory effects on underpinning pathways such as the glutamatergic and serotonergic systems is one novel approach. OBJECTIVE: To assess the effectiveness and safety of a purpose-formulated combination of nutraceuticals in treating OCD: N-acetyl cysteine, L-theanine, zinc, magnesium, pyridoxal-5' phosphate, and selenium. METHODS: A 20-week open label proof-of-concept study was undertaken involving 28 participants with treatment-resistant DSM-5-diagnosed OCD, during 2017 to 2020. The primary outcome measure was the Yale-Brown Obsessive-Compulsive Scale (YBOCS), administered every 4 weeks. RESULTS: An intention-to-treat analysis revealed an estimated mean reduction across time (baseline to week-20) on the YBOCS total score of -7.13 (95% confidence interval = -9.24, -5.01), with a mean reduction of -1.21 points per post-baseline visit (P ≤ .001). At 20-weeks, 23% of the participants were considered "responders" (YBOCS ≥35% reduction and "very much" or "much improved" on the Clinical Global Impression-Improvement scale). Statistically significant improvements were also revealed on all secondary outcomes (eg, mood, anxiety, and quality of life). Notably, treatment response on OCD outcome scales (eg, YBOCS) was greatest in those with lower baseline symptom levels, while response was limited in those with relatively more severe OCD. CONCLUSIONS: While this pilot study lacks placebo-control, the significant time effect in this treatment-resistant OCD population is encouraging and suggests potential utility especially for those with lower symptom levels. Our findings need to be confirmed or refuted via a follow-up placebo-controlled study.

Acceptability and efficacy of partner notification for curable sexually transmitted infections in sub-Saharan Africa: A systematic review.

Comprehensive case management of sexually transmitted infections (STIs) includes partner notification. We reviewed the recent literature evaluating the acceptability and efficacy of partner notification strategies (i.e. direct patient referral, provider referral, or expedited partner treatment) for curable STIs in sub-Saharan Africa. We conducted a systematic search following PRISMA guidelines: published January 2008 to June 2017 in the English language, study in sub-Saharan Africa, and discussion of any curable STI with an outcome on partner notification. We searched six electronic databases, conference abstracts, online clinical trial registries, and article bibliographies. The results showed that out of the 74 identified articles, 55 did not meet inclusion criteria. Of the 11 studies evaluating direct patient referral, the proportion of index cases ( n = 4163) who successfully notified sex partner(s) was 53% (range 23-95%). Among those who notified ( n = 1727), 25% (range 0-77%) had partner(s) that sought evaluation (95% CI 0.51-0.54; 95% CI 0.23-0.27). Both provider referral and expedited partner treatment had higher proportions of partner(s) who sought treatment ( n = 208, 69% and n = 44, 84%, respectively). Direct patient referral is the most commonly used and evaluated partner notification strategy for STIs in sub-Saharan Africa with mixed success. We recommend future research to investigate other strategies such as expedited partner treatment.

Deep brain stimulation for severe treatment-resistant obsessive-compulsive disorder: An open-label case series.

OBJECTIVE: Deep brain stimulation can be of benefit in carefully selected patients with severe intractable obsessive-compulsive disorder. The aim of this paper is to describe the outcomes of the first seven deep brain stimulation procedures for obsessive-compulsive disorder undertaken at the Neuropsychiatry Unit, Royal Melbourne Hospital. The primary objective was to assess the response to deep brain stimulation treatment utilising the Yale-Brown Obsessive Compulsive Scale as a measure of symptom severity. Secondary objectives include assessment of depression and anxiety, as well as socio-occupational functioning. METHODS: Patients with severe obsessive-compulsive disorder were referred by their treating psychiatrist for assessment of their suitability for deep brain stimulation. Following successful application to the Psychosurgery Review Board, patients proceeded to have deep brain stimulation electrodes implanted in either bilateral nucleus accumbens or bed nucleus of stria terminalis. Clinical assessment and symptom rating scales were undertaken pre- and post-operatively at 6- to 8-week intervals. Rating scales used included the Yale-Brown Obsessive Compulsive Scale, Obsessive Compulsive Inventory, Depression Anxiety Stress Scale and Social and Occupational Functioning Assessment Scale. RESULTS: Seven patients referred from four states across Australia underwent deep brain stimulation surgery and were followed for a mean of 31 months (range, 8-54 months). The sample included four females and three males, with a mean age of 46 years (range, 37-59 years) and mean duration of obsessive-compulsive disorder of 25 years (range, 15-38 years) at the time of surgery. The time from first assessment to surgery was on average 18 months. All patients showed improvement on symptom severity rating scales. Three patients showed a full response, defined as greater than 35% improvement in Yale-Brown Obsessive Compulsive Scale score, with the remaining showing responses between 7% and 20%. CONCLUSION: Deep brain stimulation was an effective treatment for obsessive-compulsive disorder in these highly selected patients. The extent of the response to deep brain stimulation varied between patients, as well as during the course of treatment for each patient. The results of this series are comparable with the literature, as well as having similar efficacy to ablative psychosurgery techniques such as capsulotomy and cingulotomy. Deep brain stimulation provides advantages over lesional psychosurgery but is more expensive and requires significant multidisciplinary input at all stages, pre- and post-operatively, ideally within a specialised tertiary clinical and/or academic centre. Ongoing research is required to better understand the neurobiological basis for obsessive-compulsive disorder and how this can be manipulated with deep brain stimulation to further improve the efficacy of this emerging treatment.

Emotion regulation difficulties in obsessive-compulsive disorder.

OBJECTIVE: Emotion regulation difficulties are implicated in psychological disorders but their role in obsessive-compulsive disorder (OCD) is unclear. Two studies examining these difficulties in OCD are presented. METHOD: A community sample (Study 1; n = 306) and a clinical OCD sample (Study 2; n = 59) completed the Difficulties in Emotion Regulation Scale (DERS) and measures of depression, anxiety, and OCD. In Study 2, the OCD sample was compared to a matched control group (n = 59, selected from Study 1). RESULTS: In Study 1, OCD was positively correlated with DERS total and subscale scores, and the DERS significantly predicted OCD severity even after accounting for age, gender, depression, and anxiety. In Study 2, emotion regulation difficulties were significantly higher in the clinical sample compared to the matched control group, even after accounting for depression and anxiety. CONCLUSION: Results showed that emotion regulation difficulties in OCD cannot simply be attributed to mood difficulties. Theoretical and treatment implications are discussed.

N-Acetyl Cysteine (NAC) in the Treatment of Obsessive-Compulsive Disorder: A 16-Week, Double-Blind, Randomised, Placebo-Controlled Study.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a disabling mental illness for which pharmacological and psychosocial interventions are all too often inadequate. Recent preclinical and clinical studies have implicated dysfunction of glutamatergic neurotransmission in the pathophysiology of OCD. The amino acid-based nutraceutical N-acetyl cysteine (NAC) is a safe and readily available agent that has been found to modify the synaptic release of glutamate in subcortical brain regions via modulation of the cysteine-glutamate antiporter. OBJECTIVE: The aim of this study was to assess the efficacy and safety of NAC in treating OCD. METHODS: A 16-week, double-blind, placebo-controlled, randomised trial using 3 g/day of NAC (1.5 g twice daily) in 44 participants (aged 18-70 years) with Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5)-diagnosed OCD, during 2013-2015. The primary outcome measure was the Yale-Brown Obsessive Compulsive Scale (YBOCS), conducted every 4 weeks. RESULTS: Analysis of the full sample (intention-to-treat) with repeated measures mixed linear modelling revealed a nonsignificant time × treatment interaction for the YBOCS scale total score (p = 0.39). A per-protocol analysis removing protocol violators also failed to show a significant time × treatment interaction for YBOCS total score (p = 0.15). However, a significant time × treatment interaction was observed for the YBOCS 'Compulsions' subscale in favour of NAC (p = 0.013), with a significant reduction observed at week 12 (dissipating at week 16). At 16 weeks, only four (20%) participants were considered 'responders' (YBOCS ≥35% reduction at endpoint) versus four (27%) in the placebo group. The NAC was well-tolerated, aside from more cases of heartburn occurring compared with placebo (p = 0.045). CONCLUSION: Further research involving NAC for OCD may require larger samples to detect moderate or small effect sizes, involve dosage or formulation differences, use in concert with exposure therapy, or an additional post-study observational period to mitigate study withdrawal. TRIAL REGISTRATION: ACTRN12613000310763.

N-acetyl cysteine in the treatment of obsessive compulsive and related disorders: a systematic review.

OBJECTIVE: Obsessive compulsive and related disorders are a collection of debilitating psychiatric disorders in which the role of glutamate dysfunction in the underpinning neurobiology is becoming well established. N-acetyl cysteine (NAC) is a glutamate modulator with promising therapeutic effect. This paper presents a systematic review of clinical trials and case reports exploring the use of NAC for these disorders. A further objective was to detail the methodology of current clinical trials being conducted in the area. METHODS: PubMed, Web of Science and Cochrane Library Database were searched for human clinical trials or case reports investigating NAC in the treatment of obsessive compulsive disorder (OCD) or obsessive compulsive related disorders. Researchers with known involvement in NAC studies were contacted for any unpublished data. RESULTS: Four clinical trials and five case reports/series were identified. Study durations were commonly 12-weeks, using 2,400-3,000 mg/day of NAC. Overall, NAC demonstrates activity in reducing the severity of symptoms, with a good tolerability profile and minimal adverse effects. Currently there are three ongoing randomized controlled trials using NAC for OCD (two adults and one pediatric), and one for excoriation. CONCLUSIONS: Encouraging results have been demonstrated from the few pilot studies that have been conducted. These results are detailed, in addition to a discussion of future potential research.

Obsessive-compulsive disorder--the role of the GP.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a mental illness that causes high levels of morbidity and is commonly associated with long delays between onset of symptoms and access to diagnosis and treatment. OBJECTIVE: To address some of the key clinical questions about detecting and managing OCD from the general practice perspective. DISCUSSION: General practitioners play a crucial role in recognising OCD, in facilitating timely access to evidence-based therapies and providing ongoing follow-up and support. Exposure and response prevention, and selective serotonin re-uptake inhibitors have the strongest evidence for efficacy in patients with OCD.

Experimental characterization and computational study of unique C,N-chelated lithium dianions.

The structure of a unique C,N-chelated dilithio dianion has been established as a solvated monomeric species using a combination of NMR and computational techniques. The highly ordered structure of the dianion may be important in its reactivity in an oxidative C-N bond-forming process.

Total synthesis of (+)-lyconadin A and related compounds via oxidative C-N bond formation.

The formation of carbon-nitrogen (C-N) bonds is a fundamental bond construction in organic synthesis and is indispensable for the synthesis of alkaloid natural products. In the context of the synthesis of the architecturally complex Lycopodium alkaloid lyconadin A, we have discovered a highly efficient oxidative C-N bond forming reaction that relies on the union of a nitrogen anion and a carbon anion. Empirical evidence amassed during our synthetic studies suggests that the mechanism of the C-N bond forming process encompasses polar as well as radical processes. Herein, we present our study of this novel C-N bond forming reaction and its application to the enantioselective total synthesis of lyconadin A and related derivatives.

A randomized controlled trial of a novel mixed monoamine reuptake inhibitor in adults with ADHD.

BACKGROUND: NS2359 is a potent reuptake blocker of noradrenalin, dopamine, and serotonin. The aim of the study was to investigate the efficacy, safety and cognitive function of NS2359 in adults with a DSM IV diagnosis of ADHD. METHODS: The study was a multi-centre, double-blind, randomized placebo-controlled, parallel group design in outpatient adults (18-55 years) testing 0.5 mg NS2359 vs. placebo for 8 weeks. Multiple assessments including computerized neuropsychological evaluation were performed. RESULTS: There was no significant difference between NS2359 (n = 63) versus placebo (n = 63) on the primary outcome measure reduction in investigator rated ADHD-RS total score (7.8 versus 6.4; p < 0.45). However, in subjects with the inattentive subtype, there were significantly more responders in the NS2359 group compared to placebo (41% versus 7%; p < 0.01). For all secondary variables (ADHD-RS patient rated; The Conners Adult ADHD Scale; The Brown Adult Scale, and CGI-improvement scale) there were no significant differences between the two groups; however, in the inattentive subgroup, the response to treatment was significantly larger than to placebo. NS2359 improved composite factor scores of attention, episodic- and working memory. No serious adverse events were reported with insomnia, headaches and loss of appetite most commonly reported as side effects. CONCLUSION: No overall effect of NS2359 was found on overall symptoms of ADHD. There was also a modest signal of improvement in the inattentive adults with ADHD and cognition warranting further exploration using differing doses.

Unified strategy for the synthesis of the "miscellaneous" lycopodium alkaloids: total synthesis of (+/-)-lyconadin A.

Total synthesis of the Lycopodium alkaloid lyconadin A was achieved in 18 steps starting from a readily available vinylogous ester and bromopicoline. The key step in the total synthesis is a proximity-driven oxidative C-N bond-forming reaction that yields the lyconadin pentacycle from a tetracyclic precursor. The key tetracycle, which has been prepared for the first time, is a versatile intermediate that may be utilized for the total synthesis of a variety of Lycopodium alkaloids. Critical to the success of this plan was the efficient preparation of a pyridine-annulated cycloheptadiene tricycle that promises to be a general strategy to access a variety of seven-membered ring containing natural products.

Gender differences in 2 clinical trials of adults with attention-deficit/hyperactivity disorder: a retrospective data analysis.

INTRODUCTION: Studies show that, in childhood attention-deficit/hyperactivity disorder (ADHD), boys have the combined type with externalizing behaviors more frequently, and girls have the inattentive type with increased internalizing disorders more frequently. METHOD: This study explored gender differences in adults with ADHD in 2 large, placebo-controlled, multicenter studies conducted from 2000 to 2001. Information collected included 2 measures of ADHD, multiple psychological measures, general physical symptoms, and treatment response. RESULTS: Thirty-four percent of the subjects were female. Women were rated as more impaired on every measure of ADHD symptoms including total Conners' Adult ADHD Rating Scale-Investigator Format (CAARS-INV), total Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS), and most subscales of both measures. More women (75%) had combined type compared with men (62%). Women showed a more complex presentation, with higher scores on the Hamilton Rating Scale for Anxiety (HAM-A) and the Hamilton Rating Scale for Depression, 17-item version (HAM-D(17)), more sleep problems, and more past DSM-IV Axis I diagnoses. Both sexes displayed substantial impairment on 3 Psychological General Well-Being Schedule factors: tension-anxiety, life satisfaction, and vitality-drive. Women experienced significantly (p = .003) greater rates of emotional dysregulation (37%) versus men (29%) as defined by a cluster of symptoms on the WRAADDS. The emotional dysregulation factor is derived by combining 3 symptoms--temper control, mood lability, and emotional overreactivity--from the Utah Criteria for ADHD in adults. These symptoms are considered associated symptoms in the DSM-IV description of ADHD. Women also experienced greater improvement (p = .011) on this symptom factor. CONCLUSION: In contrast to the results from childhood studies, women were more impaired than men on ADHD scales in our study. The higher level of emotional symptoms and more complicated presentation in women may obscure the diagnosis of ADHD. Thus, the assessments of adults with ADHD should include an exploration of the emotional dimensions of the illness.

ABT-089, a neuronal nicotinic receptor partial agonist, for the treatment of attention-deficit/hyperactivity disorder in adults: results of a pilot study.

BACKGROUND: This pilot study was designed to evaluate ABT-089, a neuronal nicotinic receptor partial agonist, as treatment for adult attention-deficit/hyperactivity disorder (ADHD). METHODS: Adults with ADHD received placebo, 2 mg, 4 mg, or 20 mg of ABT-089 for 2 weeks each in a randomized, double-blind, placebo-controlled, 4 x 4 Latin square design for a total of 8 weeks. In addition to the primary outcome, the Conner's Adult ADHD Rating Scale (CAARS), secondary rating scales, and neuropsychological and safety assessments were completed. RESULTS: A total of 11 adults with well-characterized ADHD completed this crossover study. ABT-089 b.i.d. was superior to placebo for the CAARS Total Symptom Score, which was the primary endpoint (placebo: 38.0 +/- 1.9; 2 mg b.i.d.: 32.2 +/- 1.9, one-tail p = .021; 4 mg b.i.d.: 33.2 +/- 1.9, p = .047; 20 mg b.i.d.: 33.5 +/- 1.9, p = .056). ABT-089 was also superior to placebo for the CAARS ADHD Index and Hyperactive/Impulsive scores and the Clinical Global Impression-ADHD Severity score. On the clinical efficacy endpoints, CAARS Total Symptom Score and CAARS Hyperactive/Impulsive score, a shallow inverted U-shaped dose-response curve was observed; however, the dose-response curve for attention and memory effects as measured by computerized cognitive testing seemed dose-linear. No clinically meaningful findings in safety assessments or side effect profile were observed. CONCLUSIONS: Data from this pilot study suggest that ABT-089 might be effective in treating adult ADHD and that it is well tolerated. On the basis of these promising results, larger, parallel-group ABT-089 studies of longer duration are warranted.

Emotional dysregulation in adult ADHD and response to atomoxetine.

BACKGROUND: Before 1980, attention-deficit/hyperactivity disorder (ADHD) was called minimal brain dysfunction and included emotional symptoms now listed as "associated features" in DSM-IV. Data from two multicenter, placebo-controlled studies with 536 patients were reexamined to assess: 1) the pervasiveness of these symptoms in samples of adults with ADHD; 2) the response of these symptoms to atomoxetine; and 3) their association with depressive/anxiety symptoms. METHODS: The Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS) was used to assess temper, affective lability, and emotional overreactivity, thus identifying patients exhibiting "emotional dysregulation." Other DSM-IV Axis I diagnoses were exclusionary. Outcome measures were the Conners' Adult ADHD Rating Scale (CAARS) and the WRAADDS. RESULTS: Thirty-two percent of the sample met post hoc criteria for emotional dysregulation and had higher baseline scores on ADHD measures, a lower response to placebo, and greater response to atomoxetine (p = .048). Symptoms of emotional dysregulation had a treatment effect (p < .001) at least as large as the CAARS (p = .002) and the total WRAADDS (p = .001). Emotional dysregulation was present in the absence of anxiety or depressive diagnosis. CONCLUSIONS: Symptoms of emotional dysregulation were present in many patients with ADHD and showed a treatment response similar to other ADHD symptoms.

Changes in symptoms and adverse events after discontinuation of atomoxetine in children and adults with attention deficit/hyperactivity disorder: a prospective, placebo-controlled assessment.

Drugs that affect neurotransmitter release can induce changes in neuroregulation during chronic administration. Thus, in addition to recurrence of symptoms of the illness, discontinuation of treatment can be associated with clinical signs and symptoms related to these changes. Atomoxetine, a new drug approved in the United States for treatment of attention deficit/hyperactivity disorder (ADHD), is associated with blockade of the presynaptic norepinephrine transporter. Because treatment of ADHD typically involves chronic treatment, the potential for production of a discontinuation syndrome as well as recurrence of symptoms upon drug discontinuation were assessed as part of the clinical development process. The effects of discontinuation of atomoxetine were assessed in children and adults with ADHD following 9 to 10 weeks of continuous therapy in 4 large studies. Symptoms of ADHD worsened following drug discontinuation but did not return to pretreatment levels. The incidence of discontinuation-emergent adverse events was low and there were no statistically significant differences between the patients abruptly discontinuing from atomoxetine and those continuing on placebo. Discontinuation of atomoxetine did not result in the development of an acute discontinuation syndrome and was well tolerated. It appears that atomoxetine may be discontinued without risk for symptom rebound or discontinuation-emergent adverse effects. Tapering of doses is not necessary when atomoxetine is discontinued.

A double-blind, placebo-controlled withdrawal trial of dexmethylphenidate hydrochloride in children with attention deficit hyperactivity disorder.

OBJECTIVES: d,l-threo-methylphenidate HCl (D,L-MPH) is the most common treatment of attention deficit hyperactivity disorder (ADHD). A previous report showed placebo-controlled efficacy for the purified d-isomer (dexmethylphenidate hydrochloride, d-MPH, Focalin) with a 2:1 potency compared to dl, and suggested a 6-hour duration of action. This study complements that report by studying the effect of placebo-controlled discontinuation and retesting the duration of action. METHODS: A 6-week, open-label titration of d-MPH (2.5-10 mg twice-a-day) was followed by a double-blind, placebo-controlled, 2-week withdrawal study of responders. RESULTS: In the open titration, 82% of the 89 enrolled patients achieved a Clinical Global Impression-Improvement (CGI-I) rating of much or very much improved. Only 5 patients discontinued for adverse events. Seventy-five patients continued into the placebo-controlled discontinuation. For the randomly assigned d-MPH (n=35) and placebo (n=40) groups, mean ages, respectively, were 10.1 +/- 2.9 and 9.9 +/- 2.7 years, 86% and 78% were male, and 70.6% and 80.0% took the ceiling dose of 10 mg twice-daily, respectively. Each group had 80% combined type ADHD and 20% inattentive type. By the end of the 2-week, placebo-masked withdrawal, significantly more placebo patients (24 of 39) than d-MPH continuers (6 of 35) relapsed (61.5% versus 17.1%, p=0.001). Compared to d-MPH continuers, placebo patients deteriorated significantly more in the 2-week period on teacher ratings of the 18 ADHD symptoms rated 0-3 (p=0.028), the 3 p.m. and 6 p.m. parent ADHD symptom ratings (p=0.0026 and p=0.0381, respectively), and clinic (2-3 p.m.) and home (6 p.m.) Math Tests (p=0.024 and p<0.0001, respectively). The 6 p.m. scores replicated the significant effect at 6 hours reported in the previous study. CONCLUSIONS: d-MPH is safe, tolerable, and effective, with a 6-hour duration of effect suggested by the significant difference from placebo at 6 hours on a double-blind discontinuation.