Practical Advice for Primary Care Clinicians on the Safe and Effective Use of Vortioxetine for Patients with Major Depressive Disorder (MDD).

Primary care clinicians have a vital role to play in the diagnosis and management of patients with major depressive disorder (MDD). This includes screening for MDD as well as identifying other possible psychiatric disorders including bipolar disorder and/or other comorbidities. Once MDD is confirmed, partnering with patients in the shared decision-making process while considering different treatment options and best management of MDD over the course of their illness is recommended. Vortioxetine has been approved for the treatment of adults with MDD since 2013, and subsequent US label updates indicate that vortioxetine may be particularly beneficial for specific populations of patients with MDD, including those with treatment-emergent sexual dysfunction and patients experiencing certain cognitive symptoms. Given these recent label updates, this prescribing guide for vortioxetine aims to provide clear and practical guidance for primary care clinicians on the safe and effective use of vortioxetine for the treatment of MDD, including how to identify appropriate patients for treatment.

Fed and Fasted Administration of a Novel Extended-Release Methylphenidate Orally Disintegrating Tablet Formulation for the Treatment of ADHD.

Extended-release methylphenidate is a first-line treatment for attention-deficit/hyperactivity disorder. A methylphenidate extended-release orally disintegrating tablet (MPH XR-ODT) has recently been developed. Here we report an open-label, randomized, 2-period, 2-treatment crossover study to determine the effect of food on the bioavailability of a single 60-mg dose of MPH XR-ODT in healthy adults. Blood samples were collected predose through 36 hours postdose. Maximum plasma concentration (Cmax ), time to maximum plasma concentration (Tmax ), terminal elimination half-life (T1/2 ), overall systemic exposure (AUClast and AUCinf ), and partial areas under the concentration curve (AUC0-3 , AUC3-7 , and AUC7-12 ) were calculated. In total, 48 participants completed the study. For total methylphenidate from MPH XR-ODT, the lower limit of the 90% confidence interval (CI) around the geometric mean ratio (GMR, fed/fasted) for Cmax was below 80%, indicating a slightly decreased rate of absorption with food, whereas the 90%CIs around the GMRs of AUClast and AUCinf were within the 80%-125% limits, suggesting no food effect on exposure. The most common adverse events (AEs) were palpitations and decreased appetite. No serious, unusual, or unexpected AEs were reported. Thus, food had no substantial effect on overall bioavailability of MPH XR-ODT, which may be an important factor for some patients.

Efficacy and Safety of SHP465 Mixed Amphetamine Salts in the Treatment of Attention-Deficit/Hyperactivity Disorder in Adults: Results of a Randomized, Double-Blind, Placebo-Controlled, Forced-Dose Clinical Study.

OBJECTIVE: The objective of this randomized, double-blind, placebo-controlled study was to evaluate the efficacy and safety of SHP465 mixed amphetamine salts (MAS) in adults with attention-deficit/hyperactivity disorder (ADHD). METHODS: Eligible adults [aged 18-55 years; meeting the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition ADHD criteria; baseline ADHD Rating Scale with Adult Prompts (ADHD-RS-AP) total scores ≥28] were randomized 1:1:1 to placebo or forced-dose SHP465 MAS (12.5 or 37.5 mg/day) for 4 weeks. The ADHD-RS-AP total score change from baseline to week 4 (primary endpoint) and Clinical Global Impressions-Improvement score at week 4 (key secondary endpoint) were assessed using linear mixed-effects models for repeated measures. Other efficacy endpoints were changes from baseline to week 4 on the ADHD-RS-AP hyperactivity/impulsivity and inattentiveness subscales and the percentage of participants categorized as improved on the dichotomized Clinical Global Impressions-Improvement. Safety and tolerability assessments were treatment-emergent adverse events, vital sign and weight changes, Columbia-Suicide Severity Rating Scale responses, and electrocardiogram results. RESULTS: Of 369 screened participants, 275 were randomized (placebo, n = 91; 12.5 mg/day of SHP465 MAS, n = 92; 37.5 mg/day of SHP465 MAS, n = 92) and 236 completed the study (placebo, n = 80; 12.5 mg/day of SHP465 MAS, n = 80; 37.5 mg/day of SHP465 MAS, n = 76). Least-squares mean (95% confidence interval) treatment differences at week 4 significantly favored SHP465 MAS over placebo for the ADHD-RS-AP total score change from baseline [12.5 mg/day: -8.1 (-11.7, -4.4), effect size = 0.67; 37.5 mg/day: -13.4 (-17.1, -9.7), effect size = 1.11; both p < 0.001] and Clinical Global Impressions-Improvement score [12.5 mg/day: -0.8 (-1.1, -0.4), effect size = 0.68; 37.5 mg/day: -1.2 (-1.6, -0.9), effect size = 1.11; both p < 0.001]. Treatment differences for the change from baseline at week 4 favored 12.5 and 37.5 mg/day of SHP465 MAS, respectively, over placebo on the ADHD-RS-AP hyperactivity/impulsivity (both nominal p < 0.001; effect size = 0.56 and 0.91) and inattentiveness (both nominal p < 0.001; effect size = 0.70 and 1.19) subscales. At the final on-treatment assessment, the percentage of participants categorized as improved on Clinical Global Impressions-Improvement was higher with both SHP465 MAS doses than with placebo (both nominal p < 0.001). Treatment-emergent adverse events reported (>5%) with SHP465 MAS were decreased appetite, dry mouth, insomnia, headache, anxiety, initial insomnia, irritability, and bruxism. Severe treatment-emergent adverse events and treatment-emergent adverse events leading to discontinuation, respectively, were reported by 8 and 12 participants (placebo, n = 2 and 0; 12.5 mg/day SHP465 MAS, n = 1 and 7; 37.5 mg/day SHP465 MAS, n = 5 and 5). At the final on-treatment assessment, mean ± standard deviation increases from baseline were observed with 12.5 and 37.5 mg/day of SHP465 MAS for pulse (3.3 ± 10.52 and 7.1 ± 11.48 bpm) and blood pressure (systolic 0.2 ± 7.24 and 1.7 ± 9.99 mmHg; diastolic 1.0 ± 7.46 and 2.8 ± 7.90 mmHg) and decreases were observed for weight (-0.97 ± 1.523 and -1.65 ± 2.333 kg), body mass index (-0.33 ± 0.519 and -0.56 ± 0.777 kg/m2), and Fridericia corrected QT interval (-3.0 ± 10.72 and -1.6 ± 13.70 ms). No participant in any treatment group had a positive response for on-study Columbia-Suicide Severity Rating Scale assessments. CONCLUSIONS: SHP465 MAS was superior to placebo in reducing ADHD symptoms, with a safety profile consistent with other long-acting stimulants. ClinicalTrials.gov Registry Number: NCT02604407.

Adjunctive brexpiprazole for the treatment of major depressive disorder.

INTRODUCTION: The lifetime prevalence of major depressive episodes in the United States is nearly 17%. Clinical trials and clinical effectiveness studies have demonstrated that many patients will fail to achieve remission using traditional monotherapy, contributing to significant morbidity and suffering. Because of this, augmentation strategies have been proposed to improve both treatment response and remission. Areas covered: Brexpiprazole is a second generation antipsychotic (SGA) approved by the US FDA in 2015 as an add-on treatment to an antidepressant medication for the treatment of adults with MDD, based on the results of two large-scale, randomized, placebo-controlled trials. It is thought to exert its antidepressant effect by a partial agonism of both the dopamine D2 and serotonin 5HT1A receptors. In addition, it also has potent antagonistic activity at 5HT2A, α1B and α2 C receptors, which may also contribute to monoamine transmission regulation. Expert Opinion: Overall, the tolerability of brexpiprazole is promising with relatively low rates of side effects and discontinuation rates, thus establishing it as a new option for the treatment of depression.

Brexpiprazole as an adjunctive treatment in young adults with major depressive disorder who are in a school or work environment.

BACKGROUND: Major depressive disorder (MDD) is a common, debilitating disorder with substantial socioeconomic burden. Many patients with MDD experience symptoms that impair functioning and productivity, often negatively affecting work or educational pursuits. This Phase 3b open-label study evaluated adjunctive brexpiprazole in young adults with MDD, who were in work or study. METHODS: Young patients (18-35 years) with MDD (inadequate responders to 1-3 antidepressant treatments [ADT] for their current episode) received brexpiprazole 1-3mg/day (target dose, 2mg/day) adjunctive to the same stable dose of ADT for 12 weeks. RESULTS: Depressive symptoms improved during treatment with adjunctive brexpiprazole (primary endpoint, least squares [LS] mean change from baseline in Montgomery-Åsberg Depression Rating Scale [MADRS] total score, -18.1 [p<0.0001]). Reductions from baseline in Sheehan Disability Scale Score (SDS; LS mean change -11.2 [p<0.0001]) and Work Limitations Questionnaire (WLQ; p<0.0001) indicated improvements in the effects of patients' symptoms on functioning (work/school, social life, and home responsibilities). Changes from baseline in additional measures supported improvements in patient functioning and depression symptoms. The most common adverse events were headache (21.3%), weight increase (17.0%), and somnolence (17.0%); reported rates of akathisia were low (6.4%). Clinically relevant increases in weight (≥7%) occurred in 10.5% of patients. LIMITATIONS: Open-label design; absence of comparator. CONCLUSIONS: Brexpiprazole may represent an effective therapy for adjunctive treatment strategy of young adults with MDD who are working or studying. The observed improvements in work/school functioning in patients with MDD, whose depression was treated with ADT+brexpiprazole, suggests potential to reduce socioeconomic burden.

Suicide Behaviors in Bipolar Disorder: A Review and Update for the Clinician.

Suicide behaviors (ideation, attempts, and completions) are unfortunately common in patients with bipolar disorder. It is estimated that 25 to 50% attempt suicide at least once during their lifetime, and 6% to 19% complete suicide. Risk factors include a family history of suicide, previous suicide attempts, younger age of onset, comorbid psychiatric illnesses, and psychological constructs like hopelessness. Pharmacologic treatment may impact suicidal behaviors, either increasing vulnerability or resilience. Clinicians need to be particularly sensitive to their patient's thoughts and beliefs about death, particularly during stressful times of life or when in a depressive/mixed episode of bipolar disorder.

The Bipolarity Index: a clinician-rated measure of diagnostic confidence.

BACKGROUND: The Bipolarity Index is a clinician-rated scale that rates cardinal features of the disorder across five domains: signs and symptoms, age of onset, course of illness, response to treatment, and family history. We tested the Index in routine clinical practice to identify the optimal cut-off for distinguishing bipolar from non-bipolar disorders. METHOD: Sequential patients in a private practice were rated with the Bipolarity Index (n=1903) at intake. Diagnoses were made with the MINI-6.0.0 International Neuropsychiatric Interview according to DSM-IV-TR criteria, except that cases of antidepressant-induced mania and hypomania were included in the bipolar group. A subset completed the self-rated Mood Disorder Questionnaire (MDQ) (n=1620) or Bipolar Spectrum Diagnostic Scale (BSDS) (n=1179). The primary analysis compared Bipolarity Index scores for bipolar vs. non-bipolar patients using receiver operator curves (ROC) to determine the optimal cut-off score. Secondary outcomes repeated this analysis with the MDQ, MDQ-7 (using only the symptomatic items of the MDQ) and BSDS. RESULTS: At a cut-off of ≥50, the Bipolarity Index had a high sensitivity (0.91) and specificity (0.90). Optimal cut-offs for self-rated scales were: MDQ: ≥7 (sensitivity 0.74, specificity 0.71); MDQ-7: ≥6 (sensitivity 0.77, specificity 0.77); BSDS: ≥12 (sensitivity 0.71, specificity 0.77). LIMITATIONS: The study utilized one rater at a single practice site; the rater was not blinded to the results of the MINI. CONCLUSION: The Bipolarity Index can enhance the clinical assessment of mood disorders and, at a score ≥50 has good sensitivity and specificity for identifying bipolar disorders.

Relationship of ADHD symptoms and global illness severity in adults treated with lisdexamfetamine dimesylate.

UNLABELLED: The relationship between attention-deficit/hyperactivity disorder (ADHD) symptoms and global clinical assessment of functionality is complex. This post-hoc analysis explores this relationship and suggests implications for patient assessment in clinical practice. Adults with ADHD on a stable lisdexamfetamine dimesylate (LDX) dose for ≥ 6 months were enrolled in a double-blind, placebo-controlled, randomized withdrawal study. Participants entered a 3-week open-label phase continuing their prior LDX dose and were then randomized to placebo or the same LDX dose for a 6-week, double-blind, randomized withdrawal phase. ADHD symptom distribution was measured by the ADHD Rating Scale IV (ADHD-RS-IV) with Adult Prompts total score reflecting DSM-IV-TR ADHD symptom criteria and severity by Clinical Global Impressions-Severity (CGI-S) ratings at study entry and at end of study. Of 123 participants enrolled in the open-label phase, 116 were included in the randomized withdrawal phase (placebo, n = 60; LDX, n = 56). As reported in a prior publication, mean (standard deviation) ADHD-RS-IV total score change from baseline (week 3) to end of study (randomized-withdrawal phase) was 16.8 (11.80) for placebo and 1.6 (8.63) for LDX. At end of study, for placebo and LDX, 5.0% and 32.1% of participants, respectively, had a CGI-S = 1, 11.7% and 35.7% had a CGI-S = 2, 11.7% and 17.9% had a CGI-S = 3, 33.3% and 7.1% had a CGI-S = 4, 35.0% and 7.1% had a CGI-S = 5, and 3.3% and 0% had a CGI-S = 6; no participants had a CGI-S = 7 (P < 0.0001). The CGI-S ratings increased (worsened) as ADHD symptom scores worsened. Post-hoc regression analysis between ADHD-RS-IV scores and CGI-S demonstrated shared variance of 47% at week 3 and 69% for both placebo and LDX at end of study. Although ADHD symptom scores demonstrate a linear relationship with global illness severity, the variance suggests that other factors not captured by symptom scales are also important in assessing patient outcomes in clinical practice. ( TRIAL REGISTRATION: ClinicalTrials.gov NCT00877487.).

Analysis of individual items on the attention-deficit/hyperactivity disorder symptom rating scale in children and adults: the effects of age and sex in pivotal trials of lisdexamfetamine dimesylate.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) symptom presentation across age and sex has not been fully elucidated. The present post hoc analyses qualitatively explored the baseline levels of ADHD symptomatology across subgroups in two clinical trials of children and adults with ADHD to elucidate differences in participant presentation. The response to treatment was examined to determine patterns of response among items of the ADHD Rating Scale IV. METHODS: Exploratory post hoc analyses of ADHD Rating Scale IV item scores were conducted on data from two 4-week placebo-controlled trials in children (6-12 years) and in adults (18-55 years) with ADHD. Baseline and endpoint mean item scores were determined for subgroups defined by age (6-9, 10-12, 18-39, and 40-55 years) and sex. RESULTS: The baseline mean item scores were generally numerically similar for all age-by-sex subgroups. The inattention (IA) items were numerically higher than hyperactivity/impulsivity (H/I) items among older children and adults. The endpoint mean item scores were numerically lower after lisdexamfetamine dimesylate treatment for IA and H/I items in all subgroups. CONCLUSION: These results suggest that regardless of age or sex, baseline IA and H/I symptom profiles were comparable; however, IA vs H/I symptoms were more severe in older participants. In all age-by-sex subgroups, IA and H/I symptoms appeared to decrease after active treatment.

Lisdexamfetamine dimesylate in adults with attention-deficit/ hyperactivity disorder who report clinically significant impairment in executive function: results from a randomized, double-blind, placebo-controlled study.

OBJECTIVE: Behavioral rating scales that assess impairments in executive function commonly associated with attention-deficit/hyperactivity disorder (ADHD) may offer advantages over neuropsychological testing. The primary objective of this study was to evaluate the efficacy of lisdexamfetamine dimesylate for executive function deficits in adults with ADHD and clinically significant executive function impairment using self-reported Behavior Rating Inventory of Executive Function-Adult version (BRIEF-A) assessments. METHOD: This randomized double-blind study, conducted between May 2010 and November 2010, screened at least 1 participant at 35 of 39 registered US clinical research sites. Adults (aged 18-55 years) with a primary ADHD diagnosis (meeting full DSM-IV-TR criteria) and executive function deficits (assessed by baseline BRIEF-A Global Executive Composite [GEC] T-scores of at least 65) were randomized to treatment with optimized lisdexamfetamine dimesylate (30 mg/d, 50 mg/d, or 70 mg/d; n = 80) or placebo (n = 81) during a 10-week double-blind treatment period. Outcome measures included the BRIEF-A scales (GEC, index, and clinical subscales). RESULTS: At week 10 or at early termination, lisdexamfetamine dimesylate was associated with significantly greater reductions from baseline in mean BRIEF-A GEC T-scores than placebo (effect size, 0.74; P < .0001) and significantly greater reductions from baseline in mean T-scores for both BRIEF-A index scales (Behavioral Regulation Index and Metacognition Index) and all 9 clinical subscales (P ≤ .0056 for all). At week 10 or at early termination, mean T-scores for BRIEF-A indexes and clinical subscales were below levels of clinically significant executive function deficits (ie, < 65) with lisdexamfetamine dimesylate treatment. The mean (SD) GEC T-score was 57.2 (14.11) for the lisdexamfetamine dimesylate group and 68.3 (17.12) for the placebo group. The safety profile of lisdexamfetamine dimesylate was consistent with other long-acting psychostimulants. CONCLUSION: Among adults with ADHD and clinically significant executive function deficits, lisdexamfetamine dimesylate was associated with significant improvements in self-reported executive function ratings. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01101022.

Clinical response and symptomatic remission in short- and long-term trials of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder.

BACKGROUND: Despite the overall high degree of response to pharmacotherapy, consensus is lacking on how to judge clinical response or define optimal treatment/remission when treating adults with attention-deficit/hyperactivity disorder (ADHD). This study examined clinical response and symptomatic remission in analyses of 2 studies of lisdexamfetamine dimesylate (LDX) in adults with ADHD. METHODS: In a 4-week, double-blind, forced-dose trial, adults with ADHD were randomized to LDX 30, 50, and 70 mg/day (mg/d) or placebo. In a second, open-label, follow-up trial, adults entering from the 4-week study were titrated to an "optimal" LDX dose (30 mg/d [n=44], 50 mg/d [n=112], and 70 mg/d [n=171]) over 4 weeks, and maintained for 11 additional months. The ADHD Rating Scale IV (ADHD-RS-IV) with adult prompts and the Clinical Global Impressions-Improvement (CGI-I) scale assessed efficacy. Clinical response was defined, post hoc, as ≥30% reduction from baseline in ADHD-RS-IV and CGI-I rating of 1 or 2; symptomatic remission was defined as ADHD-RS-IV total score ≤18. Log rank analysis examined overall significance among the treatment groups in time to response or remission. RESULTS: Four hundred and fourteen participants in the 4-week study and 345 in the open-label, extension study were included in the efficacy populations. All LDX groups improved by ADHD-RS-IV and CGI-I scores in both studies. In the 4-week study (n=414), 69.3% responded and 45.5% achieved remission with LDX (all doses); 37.1% responded and 16.1% achieved remission with placebo; time (95% CI) to median clinical response (all LDX doses) was 15.0 (15.0, 17.0) days and to remission was 31.0 (28.0, 37.0) days (P<.0001 overall). In the open-label study, with LDX (all doses), 313 (95.7%) and 278 (85.0%) of 327 participants with evaluable maintenance-phase data met criteria for response and remission, respectively. Of participants who completed dose optimization, 75.2% remained responders and 65.7% remained in remission in the 12-month study. Overall, 285 (82.6%) and 227 (65.8%) of 345 participants were responders and remitters, respectively, at their final visits. CONCLUSION: In the long-term study, with open-label, dose-optimized LDX treatment, most adults with ADHD achieved clinical response and/or symptomatic remission; almost two-thirds maintained symptomatic remission over the remaining 11 months. TRIAL REGISTRATION: Clinical Trial Numbers: NCT00334880 and NCT01070394CLINICAL TRIAL REGISTRY: clinicaltrials.gov.

The association of the effect of lithium in the maintenance treatment of bipolar disorder with lithium plasma levels: a post hoc analysis of a double-blind study comparing switching to lithium or placebo in patients who responded to quetiapine (Trial 144).

OBJECTIVES: There is no robust proof that the efficacy of lithium in the prevention of manic and depressive episodes in bipolar disorder depends on its plasma level. This analysis aimed to compare the effect of lithium within the presumed therapeutic range of 0.6-1.2 mEq/L and below 0.6 mEq/L with that of placebo. METHODS: We carried out a post hoc analysis of a double-blind trial in which patients aged ≥18 years with bipolar I disorder (DSM-IV) who had achieved stabilization from a manic, depressive, or mixed episode during open-label treatment with quetiapine were randomized to continue quetiapine or to switch to lithium or placebo for up to 104 weeks. Of patients randomized to lithium, 201 obtained median lithium levels between 0.6 and 1.2 mEq/L, and 137 obtained median lithium levels <0.6 mEq/L. Their outcomes were compared with those of patients receiving placebo (n = 404). The primary outcome was time to recurrence of any mood event; additional outcomes included time to recurrence of a manic or depressive event. RESULTS: Times to recurrence of any mood event as well as a manic or depressive event were significantly longer for the lithium 0.6-1.2 mEq/L group versus placebo and versus lithium <0.6 mEq/L, with no differences between lithium <0.6 mEq/L and placebo. CONCLUSIONS: The results support and expand previous findings that lithium should be dosed high enough to achieve plasma levels ≥0.6 mEq/L in order to achieve an effect in the prevention of both manic and depressive recurrences of bipolar I disorder. A major limitation is that the composition of the two lithium groups was not based on randomization.

Randomized clinical study of a histamine H3 receptor antagonist for the treatment of adults with attention-deficit hyperactivity disorder.

BACKGROUND: Psychostimulants, including methylphenidate and amphetamine preparations, are commonly prescribed for the treatment of attention-deficit hyperactivity disorder (ADHD) in children and adults. Histamine H3 receptors reside on non-histamine neurons and regulate other neurotransmitters (e.g. acetylcholine, noradrenaline [norepinephrine]) suggesting that H3 antagonists have the potential to improve attention and impulsivity. Research indicates that H3 receptor antagonists due to their novel mechanism of action may have a unique treatment effect offering an important alternative for the treatment of ADHD. Bavisant (JNJ-31001074) is a highly selective, orally active antagonist of the human H3 receptor with a novel mechanism of action, involving wakefulness and cognition, with potential as a treatment for ADHD. OBJECTIVE: The objective of this study was to evaluate the efficacy, safety and tolerability of three dosages of bavisant compared with placebo in adults with ADHD. STUDY DESIGN: This randomized, double-blind, placebo- and active-controlled, parallel-group, multicentre study evaluated three dosages of bavisant (1 mg/day, 3 mg/day or 10 mg/day) and two active controls in adults with ADHD. The study consisted of a screening phase of up to 14 days, a 42-day double-blind treatment phase and a 7-day post-treatment follow-up phase. Efficacy and safety assessments were performed. SETTING: The study was conducted at 37 study centres in the US from April 2009 through January 2010. PARTICIPANTS: Men and women aged 18-55 years with an established diagnosis of ADHD as confirmed by clinician and self-report diagnostic measures were enrolled. INTERVENTION: Participants were randomly assigned equally to one of six treatment groups: placebo, bavisant 1 mg/day, 3 mg/day or 10 mg/day, atomoxetine hydrochloride 80 mg/day or osmotic-release oral system (OROS) methylphenidate hydrochloride 54 mg/day. MAIN OUTCOME MEASURE: The primary efficacy endpoint was the change in the Attention Deficit Hyperactivity Disorder Rating Scale, Version IV (ADHD-RS-IV) total score from baseline (day 1) to the end of the treatment phase (day 42), and included all randomized participants who received one or more doses of study drug and had baseline and one or more post-baseline assessments (intent-to-treat [ITT] population). Safety assessments included treatment-emergent adverse events (TEAEs), laboratory tests and ECG readings. RESULTS: 430 participants were randomized, 424 received one or more doses of study medication and 335 (78%) of those randomized completed the study. Study participants had a mean age of 33.9 years and were predominantly White men. Mean treatment duration ranged from 31.4 to 38.8 days across groups. Mean change from baseline in the total ADHD-RS-IV score at day 42 (primary efficacy endpoint) was -8.8 in the placebo group versus -9.3, -11.2 and -12.2 in the bavisant 1 mg/day, 3 mg/day and 10 mg/day groups, respectively; the change in the 10 mg/day group was not statistically superior to placebo (p=0.161), and hence statistical comparisons of the 1 mg/day and 3 mg/day groups with placebo based on a step-down closed testing procedure were not performed. Mean change from baseline in the total ADHD-RS-IV score at day 42 was superior to placebo in the atomoxetine (-15.3) and OROS methylphenidate (-15.7) groups (p<0.005). Secondary efficacy assessments demonstrated a similar pattern with a non-significant trend towards improvement in the bavisant groups. The two lower dosages showed a good tolerability profile, but the higher dosage of bavisant was less well tolerated, as evidenced by the incidence of total TEAEs (61.8%, 82.4%, 89.0%), and discontinuations due to TEAEs (4.4%, 7.4%, 19.2%) in the bavisant 1 mg/day, 3 mg/day and 10 mg/day groups, respectively, compared with 58.9% and 2.7%, respectively on placebo. In the atomoxetine and OROS methylphenidate groups, the incidence of total TEAEs was 83.8% and 82.4% and discontinuations due to TEAEs was 10.8% and 8.8%, respectively. CONCLUSION: Bavisant, a highly selective, wakefulness-promoting H3 antagonist, did not display significant clinical effectiveness in the treatment of adults with ADHD. CLINICAL TRIAL REGISTRATION NUMBER: NCT00880217.

Efficacy of extended release quetiapine fumarate monotherapy in patients with major depressive disorder: a pooled analysis of two 6-week, double-blind, placebo-controlled studies.

Prospectively planned pooled analysis evaluating the efficacy of quetiapine extended release (XR) monotherapy in major depressive disorder (MDD). Data were pooled from two 6-week, randomized, double-blind, placebo-controlled studies of quetiapine XR in outpatients with MDD. The primary endpoint was Montgomery-Åsberg Depression Rating Scale (MADRS) total score change from randomization at week 6. Other evaluations were MADRS response/remission, Hamilton Rating Scale for Anxiety, and subgroup analyses. A total of 968 patients were randomized to quetiapine XR, 150 mg/day (n=315), 300 mg/day (n=323), or placebo (n=330). The mean MADRS total score reductions from randomization were significant at week 6 with quetiapine XR, 150 mg/day (-14.7; P<0.001) and 300 mg/day (-14.7; P<0.001) versus placebo (-11.1), with significant reductions versus placebo from week 1 onward. Response rates (week 6): 52.7% (P<0.001) quetiapine XR 150 mg/day and 49.5% (P<0.001) quetiapine XR 300 mg/day versus placebo (33.0%). MADRS remission (score≤8; week 6): 23.5% (P=0.208) quetiapine XR 150 mg/day and 28.8% (P<0.01) quetiapine XR 300 mg/day versus placebo (19.4%). Quetiapine XR (both doses) significantly improved eight of 10 MADRS items versus placebo at week 6. The therapeutic effect of quetiapine XR was neither limited to nor driven by factors such as sex, age, or severity of depression. In patients with MDD, quetiapine XR (150 and 300 mg/day) monotherapy reduced depressive symptoms, with significant improvements compared with placebo from week 1 onward.

Continuation of quetiapine versus switching to placebo or lithium for maintenance treatment of bipolar I disorder (Trial 144: a randomized controlled study).

OBJECTIVE: Quetiapine, combined with lithium or divalproex, demonstrates efficacy in the maintenance treatment of bipolar I disorder. This study investigated the efficacy and safety of quetiapine monotherapy as maintenance treatment in bipolar I disorder compared with switching to placebo or lithium. METHOD: Patients aged ≥ 18 years with DSM-IV-diagnosed bipolar I disorder and a current or recent manic, depressive, or mixed episode received open-label quetiapine (300-800 mg/d) for 4-24 weeks. Patients achieving stabilization were randomized to continue quetiapine or to switch to placebo or lithium (0.6-1.2 mEq/L) for up to 104 weeks in a double-blind trial. Outcome measures included times to recurrence of any mood event (primary outcome measure), manic event, or depressive event. Safety assessments included adverse events and laboratory values. The study was terminated early after planned interim analysis provided positive results. The study was conducted between March 2005 and July 2007. RESULTS: Of 2,438 patients starting open-label quetiapine, 1,226 (50.3%) were randomized to double-blind treatment, including 1,172 (95.6%) in the intent-to-treat population. Time to recurrence of any mood event was significantly longer for quetiapine versus placebo (hazard ratio [HR] = 0.29; 95% CI, 0.23-0.38; P < .0001) and for lithium versus placebo (HR = 0.46; 95% CI, 0.36-0.59; P < .0001). Quetiapine and lithium significantly increased time to recurrence of both manic events (quetiapine: HR = 0.29; 95% CI, 0.21-0.40; P < .0001; lithium: HR = 0.37; 95% CI, 0.27-0.53; P < .0001) and depressive events (quetiapine: HR = 0.30; 95% CI, 0.20-0.44; P < .0001; lithium: HR = 0.59; 95% CI, 0.42-0.84; P < .004) compared with placebo. Overall rates of adverse events were generally similar between treatment groups, and safety findings for quetiapine were consistent with its known profile. CONCLUSIONS: In patients stabilized during acute quetiapine treatment, continuation of quetiapine significantly increased time to recurrence of any mood, manic, or depressive event compared with switching to placebo. Switching to lithium was also more effective than placebo for the prevention of manic and depressive events. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00314184.

A national epidemic of unintentional prescription opioid overdose deaths: how physicians can help control it.

Both the usage of prescription drugs such as opioid analgesics and benzodiazepines and overdoses involving them have increased dramatically in the United States since the 1990s. Patients using these drugs often have a combination of painful conditions, substance abuse, and other forms of mental illness. Psychiatrists and many primary care physicians might not be familiar with existing evidence-based guidelines for opioid prescribing or with programs designed to reduce the abuse of prescription drugs such as state prescription drug monitoring programs. Psychiatrists need to be informed regarding this problem to partner effectively with both pain specialists and primary care providers in their community.

Treating attention-deficit/hyperactivity disorder in adults: focus on once-daily medications.

OBJECTIVE: To review the efficacy, safety, and abuse liability of approved treatments in adults with attention-deficit/hyperactivity disorder (ADHD), with a focus on once-daily medications. DATA SOURCES: PubMed was searched for relevant studies/reviews in English from 2002 to 2011 on adult ADHD treatments. STUDY SELECTION: Keywords used in the search were ADHD, adults, and treatment. Limits included only clinical trials, meta-analyses, randomized controlled trials, and reviews including adults (aged ≥ 19 years). DATA EXTRACTION: Selection criteria returned 471 publications. Retrieved studies were excluded if they primarily focused on children, treatments not indicated for ADHD, or ADHD and comorbid conditions. DATA SYNTHESIS: An epidemiologic survey revealed that 10.9% of adults identified with ADHD had received treatment during the prior 12 months. Treatments for ADHD in adults include pharmacologic and nonpharmacologic options. US Food and Drug Administration-approved long-acting stimulants and a nonstimulant with proven efficacy and safety profiles have been developed and include osmotic-release oral system methylphenidate hydrochloride (OROS-methylphenidate), extended-release dexmethylphenidate hydrochloride, mixed amphetamine salts extended release (MAS-XR), the nonstimulant atomoxetine hydrochloride, and the prodrug lisdexamfetamine dimesylate. Long-acting stimulants differ in formulation characteristics used to achieve extended release, with OROS-methylphenidate employing an osmotic-release technology, extended-release dexmethylphenidate hydrochloride and MAS-XR using pH-dependent beads, and lisdexamfetamine dimesylate using prodrug technology. These features variably affect pharmacokinetic characteristics, duration of action, and abuse liability. While all long-acting medications have varied pharmacokinetic features, mechanism of action, and duration of effect, all are generally efficacious and safety profiles are similar. CONCLUSION: Approved long-acting treatments in adults with ADHD were effective in improving symptoms and were generally well tolerated.

Posttraumatic stress disorder screening practices: a 2010 internet assessment of customary care.

OBJECTIVE: Posttraumatic stress disorder (PTSD) is a signature injury of war among returning soldiers and US National Guard and Reserve members, with symptoms even more likely on rescreening. Studies that examine health care provider screening and referral practices outside the military for these patients are needed. The objective of this study was to assess health care provider PTSD practices and barriers to care. METHOD: A 25-item, anonymous Internet questionnaire was developed as an educational needs assessment survey based on the US Department of Veterans Affairs and Department of Defense PTSD guideline and the companion, primary care-directed PTSD Screening and Referral for Health Care Providers of the National Center for PTSD. The assessment design included patient vignettes followed by multiple-choice questions and was distributed on the Internet to health care providers free of charge and without compensation. Of 1,338 participant health care providers, mainly from primary care and mental health specialties, 507 responded to the questions. Participant privacy was maintained for the self-assessment survey, and all responses were deidentified and analyzed in aggregate. Overall participant responses and subgroups of primary care and mental health questionnaire responses were scored against guidelines. Participant data responses to survey questions were collected from August 20, 2010, to October 3, 2010. RESULTS: Gaps in screening skills compared with guidelines were shown, as PTSD diagnosis questions were correctly answered by 51% of primary care and 56% of mental health providers. Real-world screening and referral differed from guidelines, as only 24% of primary care and 48% of mental health providers have a system in place to routinely screen for mental health in their patients who are returning service members. Only 25% of primary care providers had access to referral to mental health services, showing large gaps in care. Stigma associated with mental disorders was the practice barrier most frequently cited by health care providers. CONCLUSIONS: The study identified gaps in PTSD screening and linkage to care among health care providers. Further training efforts and resources are needed to screen patients and to reduce barriers to care.

How do you choose a second-line treatment option for depression?

A majority of patients with major depression do not remit or adequately respond to initial antidepressant therapy. When response is insufficient, a diagnosis of depression and any comorbidities should be confirmed, treatment adherence should be established, and antidepressant dosages should be optimized as tolerated. If response is still insufficient, then implementing second-line treatment strategies is warranted. Second-line strategies of switching to or combining/augmenting the initial agent with one of a variety of antidepressant medications and/or psychotherapies improves remission rates, although no single approach or agent has demonstrated clear superiority over any other. Second-line treatment selections should be driven by safety considerations, patients' symptom profiles, and patient preference. Comorbid medical conditions, especially cardiac and cerebrovascular complications, and potential drug-drug interactions should be considered when making treatment decisions.

A double-blind, placebo-controlled study of quetiapine and paroxetine as monotherapy in adults with bipolar depression (EMBOLDEN II).

OBJECTIVE: The aim of this study was to evaluate the efficacy and tolerability of quetiapine and paroxetine monotherapy for major depression in bipolar disorder. METHOD: 740 patients (478 bipolar I, 262 bipolar II) with major depressive episodes (DSM-IV) were randomly assigned to quetiapine 300 mg/d (n = 245), quetiapine 600 mg/d (n = 247), paroxetine 20 mg/d (n = 122), or placebo (n = 126) for 8 weeks. The primary end point was the change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score. The study was conducted from May 2005 to May 2007. RESULTS: Mean MADRS score change from baseline at 8 weeks was -16.19 for quetiapine 300 mg, -16.31 for quetiapine 600 mg, -13.76 for paroxetine, and -12.60 for placebo (P < .001 for both quetiapine doses, P = .313 for paroxetine, vs placebo). Quetiapine-treated (both doses), but not paroxetine-treated, patients showed significantly greater improvements (P < or = .05) in most secondary outcomes measures at week 8 versus the placebo group. Paroxetine significantly improved Hamilton Anxiety Rating Scale scores versus placebo (P < .05) but not MADRS or Hamilton Depression Rating Scale (HDRS) scores. Both quetiapine doses were associated with greater improvements than paroxetine for MADRS and HDRS scores. The most common adverse events were dry mouth, somnolence, sedation, and dizziness with quetiapine (both doses) and dry mouth, sedation, headache, insomnia, and nausea with paroxetine. The incidence of treatment-emergent mania/hypomania was lower with quetiapine compared with paroxetine and placebo. CONCLUSIONS: Quetiapine (300 or 600 mg/d), but not paroxetine, was more effective than placebo for treating acute depressive episodes in bipolar I and II disorder. Quetiapine treatment was generally well tolerated. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00119652.