Considerations when selecting an antidepressant: a narrative review for primary care providers treating adults with depression.

Major depressive disorder (MDD) is a debilitating mental disorder that can be treated with a number of different antidepressant therapies, each with its own unique prescribing considerations. Complicating the selection of an appropriate antidepressant for adults with MDD is the heterogeneity of clinical profiles and depression subtypes. Additionally, patient comorbidities, preferences, and likelihood of adhering to treatment must all be considered when selecting an appropriate therapy. With the majority of prescriptions being written by primary care practitioners, it is appropriate to review the unique characteristics of all available antidepressants, including safety considerations. Prior to initiating antidepressant treatment and when patients do not respond adequately to initial therapy and/or exhibit any hypomanic or manic symptoms, bipolar disorder must be ruled out, and evaluation for psychiatric comorbidities must be considered as well. Patients with an inadequate response may then require a treatment switch to another drug with a different mechanism of action, combination, or augmentation strategy. In this narrative review, we propose that careful selection of the most appropriate antidepressant for adult patients with MDD based on their clinical profile and comorbidities is vital for initial treatment selection.Strategies must be considered for addressing partial and inadequate responses as well to help patients achieve full remission and sustained functional recovery. This review also highlights data for MDD clinical outcomes for which gaps in the literature have been identified, including the effects of antidepressants on functional outcomes, sleep disturbances, emotional and cognitive blunting, anxiety, and residual symptoms of depression.

Major depressive disorder (MDD) is a leading cause of disability worldwide and can affect each patient differently. Antidepressants play a critical role in treatment; however, with multiple antidepressant options available, it is important that providers select the best fit for each patient. Rather than use a "one size fits all" approach, it is important to consider each patient's symptoms, medical and psychiatric comorbidities, as well as their treatment preferences. A clear summary of each antidepressant's distinctive characteristics is essential for providers to select antidepressants to best match each patient's needs.This narrative review aims to discuss the latest information on available antidepressants, including their risks and benefits and how they impact symptoms of MDD such as sleep disturbances, anxiety, emotional blunting, and changes in cognition, as well as different treatment goals, such as the ability to function in everyday life. This information can guide clinical practice recommendations and further enable shared decision-making between the provider and patient, incorporating individual treatment needs and preferences.In addition, many patients do not reach their treatment goals with the first antidepressant or may continue to have symptoms of depression after treatment. This review discusses strategies to increase the likelihood of symptom improvement and creates awareness of patient-specific considerations.Overall, careful, personalized selection of antidepressant treatment is critical for finding the right balance of maximized antidepressant effect with minimized side effects, leading to the best possibility for patients to tolerate the medication and ultimately helping patients reach their treatment goals.

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.

A 12-Month Open-Label Extension Study of the Safety and Tolerability of Lisdexamfetamine Dimesylate for Major Depressive Disorder in Adults.

PURPOSE/BACKGROUND: Psychostimulant augmentation is considered a potential treatment strategy for individuals with major depressive disorder who do not adequately respond to antidepressant monotherapy. The primary objective of this 12-month open-label extension study was to evaluate the safety and tolerability of lisdexamfetamine dimesylate (LDX) as augmentation therapy to an antidepressant in adults with major depressive disorder. METHODS/PROCEDURES: Eligible adults who completed 1 of 3 short-term antecedent LDX augmentation of antidepressant monotherapy studies were treated with dose-optimized LDX (20-70 mg) for up to 52 weeks while continuing on the index antidepressant (escitalopram, sertraline, venlafaxine extended-release, or duloxetine) assigned during the antecedent short-term studies. Safety and tolerability assessments included the occurrence of treatment-emergent adverse events and vital sign changes. FINDINGS/RESULTS: All 3 antecedent studies failed to meet the prespecified primary efficacy endpoint, so this open-label study was terminated early. Headache (15.5% [241/1559]), dry mouth (13.6% [212/1559]), insomnia (13.1% [204/1559]), and decreased appetite (12.1% [189/1559]) were the most frequently reported treatment-emergent adverse events. The greatest mean ± SD increases observed for systolic and diastolic blood pressure and for pulse were 2.6 ± 10.85 and 1.7 ± 7.94 mm Hg and 6.9 ± 10.27 bpm, respectively. Monitoring determined that less than 1% of participants experienced potentially clinically important changes in systolic blood pressure (10 [0.6%]), diastolic blood pressure (8 [0.5%]), or pulse (6 [0.4%]). IMPLICATIONS/CONCLUSIONS: The overall safety and tolerability of long-term LDX augmentation of antidepressant monotherapy was consistent with the profiles of the short-term antecedent studies, with no evidence of new safety signals.

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.

Treatment With Lisdexamfetamine Dimesylate Improves Self- and Informant-Rated Executive Function Behaviors and Clinician- and Informant-Rated ADHD Symptoms in Adults: Data From a Randomized, Double-Blind, Placebo-Controlled Study.

OBJECTIVE: To examine the level of agreement between self- and observer-reported ratings of ADHD symptoms and executive function (EF) behaviors in adults with moderate to severe ADHD and EF deficits. METHOD: During a 10-week, randomized, double-blind, placebo-controlled study, the effect of lisdexamfetamine dimesylate (LDX) on EF was assessed by self-report and informant report (Behavior Rating Inventory of Executive Function-Adult Version), and ADHD symptoms were assessed by clinician- and informant-rated scales (ADHD Rating Scale IV with adult prompts and Conners' Adult ADHD Rating Scales-Observer Report: Short Version, respectively). Post hoc analysis used Pearson correlations to assess relationships between self- and informant-rated EF and clinician- and informant-rated ADHD symptoms. RESULTS: Correlations between self-ratings versus informant ratings and clinician versus informant ratings were greater at Week 10/early termination (EF: placebo [0.5231-0.6085], LDX [0.3543-0.5167]; ADHD symptoms: placebo [0.4169], LDX [0.4004]) versus baseline (EF: placebo [0.3208-0.5023], LDX [0.2852-0.3439]; ADHD symptoms: placebo [0.1511], LDX [-0.0408]). CONCLUSION: LDX improved EF and ADHD symptoms, based on participant, informant, and clinician ratings. Increased rater agreement over time may reflect improved symptom awareness.

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.

Lisdexamfetamine dimesylate augmentation for adults with major depressive disorder and inadequate response to antidepressant monotherapy: Results from 2 phase 3, multicenter, randomized, double-blind, placebo-controlled studies.

BACKGROUND: The efficacy, safety, and tolerability of lisdexamfetamine dimesylate (LDX) augmentation of antidepressant monotherapy in adults with major depressive disorder (MDD) from two phase 3 studies are reported. METHODS: Across study 1 (placebo, n=201; LDX, n=201) and study 2 (placebo, n=213; LDX, n=211), most participants (placebo and LDX) in the safety analysis set were female (study 1: 66.2% and 64.2%; study 2: 67.1% and 66.8%); mean±SD ages were 41.8±12.04 with placebo and 42.2±12.32 with LDX in study 1 and 42.6±11.41 with placebo and 42.0±11.63 with LDX in study 2. Participants (18-65 y) had DSM-IV-TR-diagnosed MDD and lead-in baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total scores ≥24. Eight-week antidepressant lead-in phases prospectively assessed antidepressant response. Then, 8 weeks of randomized (1:1), double-blind treatment with dose-optimized LDX (20-70mg) or placebo in participants exhibiting inadequate antidepressant monotherapy responses (augmentation baseline MADRS total scores ≥18 and <50% MADRS total score reductions from lead-in baseline to augmentation baseline) was initiated. The primary endpoint was MADRS total score change from augmentation baseline to week 16. Safety and tolerability measures included the occurrence of treatment-emergent adverse events (TEAEs). RESULTS: Least squares mean (95% CI) treatment differences (LDX-placebo) for MADRS total score changes from augmentation baseline to week 16 were not statistically significant in study 1 (0.1 [-1.7, 2.0], P=0.883) or study 2 (-0.5 [-2.3, 1.3], P=0.583). The only TEAE reported by >5% of LDX participants at twice the placebo rate in both studies was dry mouth. LIMITATIONS: Limitations include the exclusion of participants with psychiatric comorbidities/active medical disorders, the inability to assess specific MDD symptom domains (eg, anhedonia, cognition) or subtypes, the use of telephone-based depression assessments, and the potential influence of placebo response. CONCLUSION: Contrary to expectations, LDX augmentation was not superior to placebo in reducing depressive symptoms in individuals with MDD exhibiting inadequate responses to antidepressant monotherapy.

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.

Assessment of the Efficacy and Safety of BMS-820836 in Patients With Treatment-Resistant Major Depression: Results From 2 Randomized, Double-Blind Studies.

Two phase 2B, randomized, double-blind studies assessed the efficacy and safety of fixed or flexible dose of triple monoamine uptake inhibitor BMS-820836 in patients with treatment-resistant depression to demonstrate whether switching to BMS-820836 was superior to the continuation of standard antidepressant treatment. Patients with a history of inadequate response to 1 to 3 adequate trials of antidepressant therapies were prospectively treated with duloxetine 60 mg/d for 8 weeks (CN162-006) or duloxetine 60 mg/d or escitalopram 20 mg/d for 7 weeks (CN162-007). Inadequate responders were randomized to continue their prospective phase treatment or switch to flexible-dose (0.5-2 mg/d; CN162-006) or fixed-dose (0.25, 0.5, 1, or 2 mg/d; CN162-007) BMS-820836 for 6 weeks. The primary end point in both studies was mean change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from randomization to study end point. BMS-820836 flexible (0.5-2 mg/d) or fixed dose of 1 mg/d or greater showed efficacy similar to the continuation of antidepressant treatment, with no statistically significant or clinically meaningful differences. In the CN162-006 study, the adjusted mean (SE) change in MADRS total score was -8.7 (0.661) and -8.1 (0.656) for BMS-820836 and duloxetine, respectively (P = 0.526). In the CN162-007 study, the adjusted mean (SE) change in MADRS total score was -7.3 (0.830) and -6.6 (0.842) for BMS-820836 of 1 and 2 mg, respectively, and -6.9 (0.602) for the continuation group (P = 0.910). Thus, BMS-820836 was well tolerated, with no evidence of dose-dependent discontinuations due to adverse events, but it failed to demonstrate superiority to the continuation of an existing antidepressant in patients with treatment-resistant depression.

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.).

Extended release quetiapine fumarate in patients with major depressive disorder: suicidality data from acute and maintenance studies.

OBJECTIVE: To prospectively analyze effects of extended release quetiapine fumarate (quetiapine XR) on suicidality in major depressive disorder (MDD). METHOD: Data were pooled from randomized, acute studies (4 monotherapy; 2 adjunct therapy) in adult patients with a DSM-IV diagnosis of MDD who were considered not to be at high risk of suicide at baseline and were receiving quetiapine XR 50 mg/d (n = 181), 150 mg/d (n = 910), or 300 mg/d (n = 685) or placebo (n = 957). Data from 1 acute monotherapy study in elderly patients receiving quetiapine XR (50-300 mg/d; n = 166) or placebo (n = 172) and maintenance data (up to 52 weeks) for patients receiving quetiapine XR (50-300 mg/d; n = 391) or placebo (n = 385) were also evaluated. Overall incidences and relative risks for suicidality (suicidal behavior/ideation) were assessed by Columbia-type review and classification. The proportion of patients with Montgomery-Asberg Depression Rating Scale (MADRS) item 10 (suicidal thoughts) score ≥ 4 was analyzed. RESULTS: Incidence of suicidality during acute treatment in adults was 1.1%, 0.7%, 0.7%, and 0.7% with quetiapine XR 50 mg/d, 150 mg/d, and 300 mg/d and placebo, respectively. The proportion of patients with MADRS item 10 score ≥ 4 during acute treatment in adults was 1.8% with quetiapine XR (all doses combined) and 2.4% with placebo. In elderly patients, the incidence of suicidality during acute treatment was 0.6% in both treatment groups; the proportion of patients with MADRS item 10 score ≥ 4 was 0% with quetiapine XR (all doses combined) and 1.2% with placebo. During maintenance treatment, the incidence of suicidality was 0.3% (n = 1) and 0.5% (n = 2) for quetiapine XR and placebo, respectively. The proportion of patients with MADRS item 10 score ≥ 4 was 4.1% with quetiapine XR in the open-label stabilization period and 0.3% with quetiapine XR and 0.5% with placebo during the randomized period. CONCLUSIONS: This analysis suggests that there is no evidence of treatment-emergent suicidality with quetiapine XR therapy in patients with MDD considered not to be at high suicide risk at baseline.

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.

Extended-release quetiapine fumarate in the treatment of patients with major depressive disorder: adjunct therapy.

Approximately half of the patients with major depressive disorder (MDD) respond insufficiently to current antidepressants, resulting in increased risk of relapse and residual symptoms. Strategies available include dose increase, combination with a second agent, switching antidepressants, adjunct treatment, psychotherapy or exercise. Efficacy and tolerability of once-daily extended-release quetiapine fumarate (quetiapine XR) adjunct to index antidepressant therapy in patients with MDD and an inadequate response to treatment were assessed in two acute studies as part of a global clinical trial program. Quetiapine XR significantly improved depressive symptoms versus placebo. Significant improvement in quality of life versus placebo was confined to elderly patients with MDD. Tolerability was consistent with the known pharmacological profile of quetiapine: the most common adverse events were dry mouth, somnolence, sedation, dizziness and fatigue. Quetiapine XR is approved in the EU, USA and several other countries worldwide as adjunctive treatment for patients with MDD and an inadequate response to previous antidepressants.

The role of extended-release quetiapine fumarate monotherapy in the treatment of patients with major depressive disorder.

Pharmacotherapy, psychotherapy and other nonpharmacological interventions are used in patients with major depressive disorder (MDD). However, 50% of the patients with MDD fail to achieve a response to first-line antidepressant treatment. In four of five acute monotherapy studies, once-daily extended-release quetiapine fumarate (quetiapine XR) significantly improved depressive symptoms compared with placebo in patients with MDD. One acute monotherapy study demonstrated that neither quetiapine XR nor escitalopram had a statistically significant separation from placebo on the primary endpoint. Quetiapine XR maintenance therapy also significantly reduced the risk of recurrence of a depressive event. No significant improvement in overall quality of life was observed versus placebo except in the acute elderly study. Tolerability findings were consistent with the known pharmacological profile of quetiapine; the most common adverse events were dry mouth, sedation, somnolence and dizziness. Quetiapine XR monotherapy has been approved as a treatment for MDD in a limited number of countries.

Self-Reported quality of life in adults with attention-deficit/hyperactivity disorder and executive function impairment treated with lisdexamfetamine dimesylate: a randomized, double-blind, multicenter, placebo-controlled, parallel-group study.

BACKGROUND: This study examined the effects of lisdexamfetamine dimesylate (LDX) on quality of life (QOL) in adults with attention-deficit/hyperactivity disorder (ADHD) and clinically significant executive function deficits (EFD). METHODS: This report highlights QOL findings from a 10-week randomized placebo-controlled trial of LDX (30-70 mg/d) in adults (18-55 years) with ADHD and EFD (Behavior Rating Inventory of EF-Adult, Global Executive Composite [BRIEF-A GEC] ≥65). The primary efficacy measure was the self-reported BRIEF-A; a key secondary measure was self-reported QOL on the Adult ADHD Impact Module (AIM-A). The clinician-completed ADHD Rating Scale version IV (ADHD-RS-IV) with adult prompts and Clinical Global Impressions-Severity (CGI-S) were also employed. The Adult ADHD QoL (AAQoL) was added while the study was in progress. A post hoc analysis examined the subgroup having evaluable results from both AIM-A and AAQoL. RESULTS: Of 161 randomized (placebo, 81; LDX, 80), 159 were included in the safety population. LDX improved AIM-A multi-item domain scores versus placebo; LS mean difference for Performance and Daily Functioning was 21.6 (ES, 0.93, P<.0001); Impact of Symptoms: Daily Interference was 14.9 (ES, 0.62, P<.0001); Impact of Symptoms: Bother/Concern was 13.5 (ES, 0.57, P=.0003); Relationships/Communication was 7.8 (ES, 0.31, P=.0302); Living With ADHD was 9.1 (ES, 0.79, P<.0001); and General Well-Being was 10.8 (ES, 0.70, P<.0001). AAQoL LS mean difference for total score was 21.0; for subscale: Life Productivity was 21.0; Psychological Health was 12.1; Life Outlook was 12.5; and Relationships was 7.3. In a post hoc analysis of participants with both AIM-A and AAQoL scores, AIM-A multi-item subgroup analysis scores numerically improved with LDX, with smaller difference for Impact of Symptoms: Daily Interference. The safety profile of LDX was consistent with amphetamine use in previous studies. CONCLUSIONS: Overall, adults with ADHD/EFD exhibited self-reported improvement on QOL, using the AIM-A and AAQoL scales in line with medium/large ES; these improvements were paralleled by improvements in EF and ADHD symptoms. The safety profile of LDX was similar to previous studies. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01101022.

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.