Paul Hammerness

A Randomized, Placebo-Controlled Trial of OROS Methylphenidate in Adults with Attention-Deficit/Hyperactivity Disorder

BACKGROUND The objective of this study was to evaluate the safety and efficacy of once-daily OROS methylphenidate (MPH) in the treatment of adults with DSM-IV attention-deficit/hyperactivity disorder (ADHD). METHODS We conducted a randomized, 6-week, placebo-controlled, parallel-design study of OROS MPH in 141 adult subjects with DSM-IV ADHD, using standardized instruments for diagnosis. OROS MPH or placebo was initiated at 36 mg/day and titrated to optimal response, depending on efficacy and tolerability, up to 1.3 mg/kg/day. RESULTS Treatment with OROS MPH was associated with clinically and statistically significant reductions in DSM-IV symptoms of inattention and hyperactivity/impulsivity relative to subjects treated with placebo. At endpoint, 66% of subjects (n = 44) receiving OROS MPH and 39% of subjects (n = 29) [corrected] receiving placebo attained our a priori definition of response of much or very much improved on the Clinical Global Impression-Improvement scale plus a >30% reduction in Adult ADHD Investigator System Report Scale score. OROS MPH was associated with small but statistically significant increases in systolic blood pressure (3.5 +/- 11.8 mm Hg), diastolic blood pressure (4.0 +/- 8.5 mm Hg), and heart rate (4.5 +/- 10.5 bpm). CONCLUSIONS These results show that treatment with OROS MPH in daily doses of up to 1.3 mg/kg/day was effective in the treatment of adults with ADHD. Because of the potential for increases in blood pressure and heart rate, subjects receiving treatment with MPH should be monitored for changes in blood pressure parameters during treatment.

Towards further understanding of the co-morbidity between attention deficit hyperactivity disorder and bipolar disorder : a MRI study of brain volumes

BACKGROUND Although attention deficit hyperactivity disorder (ADHD) and bipolar disorder (BPD) co-occur frequently and represent a particularly morbid clinical form of both disorders, neuroimaging research addressing this co-morbidity is scarce. Our aim was to evaluate the morphometric magnetic resonance imaging (MRI) underpinnings of the co-morbidity of ADHD with BPD, testing the hypothesis that subjects with this co-morbidity would have neuroanatomical correlates of both disorders. METHOD Morphometric MRI findings were compared between 31 adults with ADHD and BPD and with those of 18 with BPD, 26 with ADHD, and 23 healthy controls. The volumes (cm(3)) of our regions of interest (ROIs) were estimated as a function of ADHD status, BPD status, age, sex, and omnibus brain volume using linear regression models. RESULTS When BPD was associated with a significantly smaller orbital prefrontal cortex and larger right thalamus, this pattern was found in co-morbid subjects with ADHD plus BPD. Likewise, when ADHD was associated with significantly less neocortical gray matter, less overall frontal lobe and superior prefrontal cortex volumes, a smaller right anterior cingulate cortex and less cerebellar gray matter, so did co-morbid ADHD plus BPD subjects. CONCLUSIONS Our results support the hypothesis that ADHD and BPD independently contribute to volumetric alterations of selective and distinct brain structures. In the co-morbid state of ADHD plus BPD, the profile of brain volumetric abnormalities consists of structures that are altered in both disorders individually. Attention to co-morbidity is necessary to help clarify the heterogeneous neuroanatomy of both BPD and ADHD.

Genitourinary and Sexual Adverse Effects of Psychotropic Medication

Objective: We review the adverse effects on genitourinary and sexual function associated with antidepressants, neuroleptics, lithium, and benzodiazepines, and suggest treatment strategies that may be used for their management. Method: This article is based on systematic review of the existing literature, including more than 130 relevant articles on genitourinary and sexual effects of psychotropic medications. Results: We find that genitourinary function, including effects on continence and flow, and sexual function, including libido, erection, ejaculation and orgasm, may be altered by psychotropic administration. Many of these effects may be consequent to the impact of these medications on neurophysiologic systems. Conclusions: Genitourinary and sexual adverse effects associated with psychotropic therapy are important areas of study and clinical concern that may affect patient comfort and compliance with treatment.

Treatment of Attention-Deficit/Hyperactivity Disorder in Adolescents: A Systematic Review

IMPORTANCE Although attention-deficit/hyperactivity disorder (ADHD) is highly prevalent in adolescents and often persists into adulthood, most studies about treatment were performed in children. Less is known about ADHD treatment in adolescents. OBJECTIVE To review the evidence for pharmacological and psychosocial treatment of ADHD in adolescents. EVIDENCE REVIEW The databases of CINAHL Plus, MEDLINE, PsycINFO, ERIC, and the Cochrane Database of Systematic Reviews were searched for articles published between January 1, 1999, and January 31, 2016, on ADHD treatment in adolescents. Additional studies were identified by hand-searching reference lists of retrieved articles. Study quality was rated using McMaster University Effective Public Health Practice Project criteria. The evidence level for treatment recommendations was based on Oxford Centre for Evidence-Based Medicine criteria. FINDINGS Sixteen randomized clinical trials and 1 meta-analysis, involving 2668 participants, of pharmacological and psychosocial treatments for ADHD in adolescents aged 12 years to 18 years were included. Evidence of efficacy was stronger for the extended-release methylphenidate and amphetamine class stimulant medications (level 1B based on Oxford Centre for Evidence-Based Medicine criteria) and atomoxetine than for the extended-release α2-adrenergic agonists guanfacine or clonidine (no studies). For the primary efficacy measure of total symptom score on the ADHD Rating Scale (score range, 0 [least symptomatic] to 54 [most symptomatic]), both stimulant and nonstimulant medications led to clinically significant reductions of 14.93 to 24.60 absolute points. The psychosocial treatments combining behavioral, cognitive behavioral, and skills training techniques demonstrated small- to medium-sized improvements (range for mean SD difference in Cohen d, 0.30-0.69) for parent-rated ADHD symptoms, co-occurring emotional or behavioral symptoms, and interpersonal functioning. Psychosocial treatments were associated with more robust (Cohen d range, 0.51-5.15) improvements in academic and organizational skills, such as homework completion and planner use. CONCLUSIONS AND RELEVANCE Evidence supports the use of extended-release methylphenidate and amphetamine formulations, atomoxetine, and extended-release guanfacine to improve symptoms of ADHD in adolescents. Psychosocial treatments incorporating behavior contingency management, motivational enhancement, and academic, organizational, and social skills training techniques were associated with inconsistent effects on ADHD symptoms and greater benefit for academic and organizational skills. Additional treatment studies in adolescents, including combined pharmacological and psychosocial treatments, are needed.

An open trial of bupropion for the treatment of adults with attention-deficit/hyperactivity disorder and bipolar disorder.

BACKGROUND Despite the increasing recognition of comorbid attention-deficit/hyperactivity disorder (ADHD) and bipolar disorder (BPD) in adults, there are no prospective trials of pharmacological agents to treat ADHD in these patients. Given the efficacy of bupropion for ADHD in adults, as well as its use in the management of bipolar depression, we studied the tolerability and efficacy of sustained-release (SR) bupropion in adults with ADHD plus BPD. METHODS This was an open, prospective, 6-week trial of bupropion SR (up to 200 mg b.i.d.) in adults with DSM-IV ADHD plus historical bipolar I disorder (BPD I) (10%) or bipolar II disorder (BPD II) (90%). Adults receiving adjunct antimanic agents (mood stabilizers and antipsychotics) at baseline were included in the study. We used standardized psychiatric instruments for diagnosis and outcome. Efficacy was based primarily on the Clinical Global Impression Scale (CGI) for ADHD and the ADHD symptom checklist. RESULTS Of 36 patients entered (75% male, mean age 34 years), 30 patients (83%) completed the protocol. At end point (last observation carried forward [LOCF]) compared to baseline, treatment with bupropion SR resulted in significant reductions in the ADHD symptom checklist (-55%, z = 5.63, p <.001) and CGI severity of ADHD (-40%, z = 6.285, p <.001). Bupropion was associated with reductions in ratings of mania and depression. CONCLUSIONS The results from this open study of adults with ADHD plus BPD suggest that sustained-release bupropion may be effective in treating ADHD in the context of a lifetime diagnosis of BPD, without significant activation of mania. Further controlled trials are warranted.

An open-label trial of aripiprazole monotherapy in children and adolescents with bipolar disorder.

INTRODUCTION Aripiprazole is a novel second-generation antipsychotic approved for the treatment of bipolar disorder in adults but there is no systematic data available in pediatric bipolar disorder. METHODS This was an 8-week, open-label, prospective study of aripiprazole 9.4+/-4.2 mg/day monotherapy to assess the efficacy and tolerability of this compound in treating pediatric bipolar disorder. Assessments included the Young Mania Rating Scale, Clinical Global Impressions-Improvement scale, and Brief Psychiatric Rating Scale. Adverse events were assessed through spontaneous self-reports, vital signs weight monitoring, and laboratory analysis. RESULTS Fifteen of the 19 bipolar youth (79%) completed the study. Aripiprazole treatment was associated with clinically and statistically significant improvement in mean Young Mania Rating Scale scores (-18.0+/-6.9, P<.0001). With the important exception of two cases of extrapyramidal symptoms that precipitated dropout, aripiprazole was well tolerated with no statistically significant increase in body weight (1.8+/-1.7 kg, P=.2). CONCLUSION Open-label aripiprazole treatment was beneficial in the treatment of mania in youth with bipolar disorder. Future placebo-controlled, double-blind studies are warranted.

Cardiovascular Risk of Stimulant Treatment in Pediatric Attention-Deficit/ Hyperactivity Disorder: Update and Clinical Recommendations

OBJECTIVE This review provides an update on the cardiovascular impact of therapeutic stimulant-class medication for children and adolescents with attention-deficit/hyperactivity disorder (ADHD). METHOD Relevant clinical literature was ascertained using PubMed searches limited to human studies and the English language as of May 2011. Current practice guidelines and consensus statements also were reviewed. RESULTS Stimulant-class medications for healthy children and adolescents with ADHD are associated with mean elevations in blood pressure (≤5 mmHg) and heart rate (≤10 beats/min) without changes in electrocardiographic parameters. A subset (5-15%) of children and adolescents treated may have a greater increase in heart rate or blood pressure at a given assessment or may report a cardiovascular-type complaint during stimulant treatment. It is extremely rare for a child or adolescent receiving stimulant medication to have a serious cardiovascular event during treatment, with the risk appearing similar to groups of children not receiving stimulant medication. CONCLUSIONS Clinicians should adhere to current recommendations regarding the prescription of stimulant medications for youth with ADHD. Scientific inquiry is indicated to identify patients at heightened risk and to continue surveillance for the longer-term cardiovascular impact of these agents.

A Randomized, 3-phase, 34-week, Double-blind, Long-term Efficacy Study of Osmotic-release Oral System-methylphenidate in Adults With Attention-deficit/hyperactivity Disorder

We conducted a 3-phase, double-blind, placebo-controlled, parallel study design of osmotic-release oral system (OROS)-methylphenidate (MPH) in adults (19-60 years of age) with attention deficit/hyperactivity disorder as classified by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Phase 1 of the study was a 6-week, acute efficacy trial (n = 223), phase 2 was a 24-week, double-blind continuation study of responders (n = 96), and phase 3 was a double-blind, placebo-controlled, 4-week discontinuation study (n = 23). The mean daily dosage at phase 1 endpoint was 78.4 ± 31.7 mg (0.97 ± 0.32 mg/kg) OROS-MPH and 96.6 ± 26.5 mg (1.16 ± 0.19 mg/kg) placebo (P < 0.0001). Clinical response at phase 1 endpoint was significantly greater in the OROS-MPH group (62%, n = 67 vs 37%, n = 41; P < 0.001) and was maintained throughout 24 weeks of double-blind treatment. With double-blind, placebo-controlled discontinuation, however, there was no statistically significant difference in the rate of relapse between OROS-MPH responders randomized to placebo and those randomized to continue active treatment (18%, n = 2 vs 0%, n = 0; P = 0.1). As expected, decreased appetite, insomnia, being tense/jittery, mucosal dryness, and neurological symptoms were statistically significantly associated with OROS-MPH treatment. More work is needed to be conducted with larger samples being followed to study completion to better understand the long-lasting impact of pharmacotherapy for adult attention-deficit/hyperactivity disorder.

Preliminary examination of the reliability and concurrent validity of the attention-deficit/hyperactivity disorder self-report scale v1.1 symptom checklist to rate symptoms of attention-deficit/hyperactivity disorder in adolescents.

OBJECTIVE To validate the attention-deficit/hyperactivity disorder (ADHD) Self-Report Scale (ASRS) v1.1 Symptom Checklist versus the clinician-administered ADHD Rating Scale (ADHD-RS) in adolescents with ADHD. METHOD A total of 88 adolescents with ADHD aged 13-17 years participated in the study. The study was completed in one or two visits, 1-9 weeks apart. At each visit, participants completed the ASRS v1.1 Symptom Checklist, after which raters administered the ADHD-RS. Internal consistency of the ASRS v1.1 Symptom Checklist was assessed by Cronbachs alpha (Cronbachs α). Concurrent validity between the scales was assessed using Pearsons correlation coefficients. Item-by-item reliability between the scales was assessed by the Kappa coefficient of agreement. RESULTS The mean age of participants was 14.9±1.5 SD years. 76.1% (n=67) were male. 73.9% (n=65) were currently receiving medication for ADHD. Internal consistency of ASRS v1.1 Symptom Checklist items was high, with Cronbachs α coefficients of 0.93 at Visit 1 and 0.94 at Visit 2. Pearsons correlation coefficients between the ASRS v1.1 Symptom Checklist and ADHD-RS were highly significant at Visit 1 (r=0.72, p<0.0001) and Visit 2 (r=0.73, p<0.0001). There was moderate item-by-item agreement between individual items on the scales (% agreement: 35.2%-63.4%) with statistically significant kappa coefficients for 17 of the 18 items. CONCLUSION The ASRS v1.1 Symptoms Checklist showed high internal consistency and high concurrent validity with the clinician-administered ADHD-RS in adolescents with ADHD. Results of this study suggest that the ASRS v1.1 Symptom Checklist is an internally consistent self-report scale for the assessment of adolescent ADHD and is moderately associated with a concurrently administered clinician measure of ADHD symptoms.

Is oppositional defiant disorder a meaningful diagnosis in adults?: Results from a large sample of adults with ADHD.

We examined the prevalence and clinical characteristics of oppositional defiant disorder (ODD) in a sample of clinically referred adults with attention deficit hyperactivity disorder (ADHD). Subjects were consecutively referred adults with a DSM-III R/IV diagnosis of ADHD with or without ODD. Nearly half of subjects (43%) had a history of ODD. Subjects with a childhood history of ODD had increased risk for bipolar disorder, multiple anxiety disorders, and substance use disorders relative to the ADHD subjects without ODD. We concluded, as in children with ODD, adults with a childhood history of ODD have high rates of psychiatric comorbidity and more impaired psychosocial functioning than those without this condition. A better understanding of the course, phenomenology, and clinical significance of ODD in adults is needed to better understand therapeutic approaches for this disorder.