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Patients with a severe mental illness such as bipolar I disorder (BP-I) have a higher prevalence of obesity and related metabolic comorbidities than the general population. This study evaluated the impact of cariprazine on weight and blood pressure in patients with BP-I depression using electronic medical records (EMRs) from a nationally representative database.
Analyses were based on data from EMRs in the Symphony Health’s Integrated Dataverse® from March 2015 to October 2018. Patients ≥18 years of age with ≥2 cariprazine fills (first dispensing=index date) and clinical activity for ≥12 months pre-index (baseline) and ≥1 month post-index were included. Patients also had a diagnosis of BP-I depression at their most recent episode prior to cariprazine initiation. The on-treatment period spanned from the index date to the earliest of cariprazine discontinuation, a switch to another atypical or long-acting injectable antipsychotic, end of clinical activity, or end of data. Metabolic outcomes of interest were weight and blood pressure (systolic and diastolic). For each outcome, patients were required to have ≥1 measurement in both the baseline and on-treatment periods. Linear trajectories during those periods were estimated using mixed-effects models; 95% confidence intervals (CIs) were calculated using non-parametric bootstrap procedures.
In total, 1702 patients who met study eligibility criteria had ≥1 weight measurement recorded in the baseline and on-treatment periods; of these patients, 178 had bipolar I depression as their most recent episode. Patients gained an average of 2.43 kg/year during the baseline period and 0.60 (95% CI: -1.97, 3.70) kg/year during the on-treatment period. Analyses of blood pressure change (n=179) showed that cariprazine had neutral effects over the on-treatment period. Patients’ systolic blood pressure increased at 1.12 mmHg/year during baseline and decreased at -0.63 (95% CI: -3.59, 2.25) mmHg/year during the on-treatment period. For diastolic blood pressure, increases of 0.25 mmHg/year during baseline and 0.44 (95% CI: -1.65, 2.16) mmHg/year during the on-treatment period were observed.
Although patient weight was increasing prior to cariprazine initiation, a neutral weight trajectory was seen with long-term cariprazine treatment among those with a most recent BP-I depression episode. Cariprazine also had minimal impact on systolic or diastolic blood pressure. Overall, these findings are consistent with prior short- and long-term studies showing that cariprazine has a neutral weight and metabolic profile.
Tardive dyskinesia (TD) is a persistent and potentially disabling movement disorder associated with exposure to antipsychotics and other dopamine receptor blocking agents. Effective and comprehensive treatment of TD requires reducing patients’ abnormal involuntary movements without disrupting their psychiatric stability. This can be especially challenging when patients have complex psychiatric conditions (e.g., >1 psychiatric diagnosis) and are taking multiple medications. Valbenazine, a highly potent and selective vesicular monoamine transporter 2 (VMAT2) inhibitor, is approved for the once-daily treatment of TD. This post hoc analysis of two long-term studies (KINECT 3, KINECT 4) was conducted to evaluate changes in psychiatric status and clinician- and patient-reported treatment success in study participants who received valbenazine (40 or 80 mg) for 48 weeks.
Data from KINECT 3 and KINECT 4 were pooled and analyzed in participants categorized by their primary psychiatric diagnosis: schizophrenia/schizoaffective disorder (“SCHZ”) or mood disorder (“MD”). Concomitant medications needed for managing these and other psychiatric or medical conditions were allowed. Treatment success was defined as achieving a rating of “much improved” or “very much improved” at Week 48, as assessed using the Clinical Global Impression of Change-Tardive Dyskinesia (CGI-TD) and Patient Global Impression of Change (PGIC). Psychiatric stability was monitored using the following scales: Positive and Negative Syndrome Scale (PANSS) and Calgary Depression Scale for Schizophrenia (CDSS) in the SCHZ subgroup; Young Mania Rating Scale (YMRS) and Montgomery-Åsberg Depression Rating Scale (MADRS) in the MD subgroup. Suicidal ideation/behavior was monitored using the Columbia-Suicide Severity Rating Scale.
More than 75% of study participants in the SCHZ subgroup achieved treatment success with valbenazine, based on clinician assessment (CGI-TD, 79.7%) and patient self-report (PGIC, 78.0%). Mean changes from baseline to Week 48 for PANSS scores (positive symptoms [-0.7], negative symptoms [‑0.6], general psychopathology [-1.9], total [-3.2]) and CDSS total score (-0.5) indicated maintenance of psychiatric stability in the SCHZ subgroup. Similar treatment success rates were found in the MD subgroup for both CGI-TD (77.6%) and PGIC (84.5%), with mean changes from baseline in YMRS total score (-1.0) and MADRS total score (+0.3) indicating psychiatric stability was maintained. No emergence of suicidal ideation/behavior was observed during the studies.
Pooled analyses from two 48-week studies indicate that long-term treatment of TD with once-daily valbenazine resulted in substantial clinician- and patient-reported global improvements in TD, while psychiatric stability was maintained regardless of primary psychiatric condition.
Lumateperone (LUMA) is an FDA-approved antipsychotic to treat schizophrenia and depressive episodes associated with bipolar I or bipolar II disorder. An open-label study (Study 303) evaluated the safety and tolerability of LUMA in outpatients with stable schizophrenia who switched from previous antipsychotic (AP) treatment. This post hoc analysis of Study 303 investigated the safety and tolerability of LUMA stratified by previous AP in patients who switched to LUMA treatment for 6 weeks.
Adult outpatients (≥18 years) with stable schizophrenia were switched from previous AP to LUMA 42 mg once daily for 6 weeks followed by switching to another approved AP for 2 weeks follow-up. Post hoc analyses were stratified by most common previous AP: risperidone or paliperidone (RIS/PAL); quetiapine (QET); aripiprazole or brexpiprazole (ARI/BRE); olanzapine (OLA). Safety analyses included adverse events (AE), vital signs, and laboratory tests. Efficacy was assessed using the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impressions-Severity (CGI-S) scale.
The safety population comprised 301 patients, of which 235 (78.1%) were previously treated with RIS/PAL (n=95), QET (n=60), ARI/BRE (n=43), or OLA (n=37). Rates of treatment-emergent AEs (TEAEs) while on LUMA were similar between previous AP groups (44.2%-55.8%). TEAEs with incidences of ≥5% in any AP group were dry mouth, somnolence, sedation, headache, diarrhea, cough, and insomnia. Most TEAEs were mild or moderate in severity for all groups. Rates of serious TEAEs were low and similar between groups (0%–7.0%).
Statistically significant (P<.05) decreases from baseline were observed in the OLA group that switched to LUMA in total cholesterol and low-density lipoprotein cholesterol with significant decreases thereafter on LUMA. Statistically significant decreases in prolactin levels were observed in both the RIS/PAL (P<.0001) and OLA (P<.05) groups. Patients switched from RIS/PAL to LUMA showed significant (P<.05) decreases for body mass index, waist circumference, and weight. At follow-up, 2 weeks after patients switched back from LUMA to another AP, none of the decreases in laboratory parameters or body morphology observed while on LUMA maintained significance.
Those switching from QET had significant improvements from baseline at Day 42 in PANSS Total score (mean change from baseline −3.47; 95% confidence interval [CI] −5.27, −1.68; P<.001) and CGI-S Total score (mean change from baseline −0.24; 95% CI, −0.38, −0.10; P<.01).
In outpatients with stable schizophrenia, LUMA 42 mg treatment was well tolerated in patients switching from a variety of previous APs. Patients switching from RIS/PAL or OLA to LUMA had significant improvements in cardiometabolic and prolactin parameters. These data further support the favorable safety, tolerability, and efficacy of LUMA in patients with schizophrenia.
Amphetamines are a first-line treatment for ADHD. The dextroamphetamine transdermal system (d-ATS) was developed as an alternative to oral amphetamine formulations. A randomized controlled trial of d-ATS in children and adolescents with ADHD was conducted, and its primary and key secondary endpoints were met. Here, we report secondary endpoints of the study, further assessing the efficacy and safety of d-ATS.
This study comprised a 5-week, open-label dose optimization period (DOP) followed by a 2-week, randomized, cross-over double-blind treatment period (DBP). All eligible patients received d-ATS 5 mg/9 h and were evaluated weekly for a possible dose increase to 10 mg/9 h, 15 mg/9 h, and 20 mg/9 h. Once reached, the optimal dose was maintained for the DOP and utilized during the DBP. Secondary objectives for this study included assessment of efficacy via Permanent Product Measure of Performance-Attempted and -Correct (PERMP-A, PERMP-C), ADHD-RS-IV, Conners Parent Rating Scale Revised Short Form (CPRS-R:S), and Clinical Global Impression (CGI) scores in a laboratory classroom setting. Efficacy was analyzed using a mixed-model repeated-measures (MMRM) approach. Safety assessments included treatment-emergent adverse events (TEAEs) and dermal safety.
In total, 110 patients were enrolled in the DOP, and 106 patients were randomized in the DBP. Patients receiving d-ATS demonstrated significant improvement vs placebo in PERMP-A and -C scores in the DBP consistently from 2 to 12 hours post-dose (P < .001 for all timepoints). ADHD-RS-IV total scores improved during the DOP and improved further during the DBP, with a least-squares mean (95% CI) difference for d-ATS vs placebo of −13.1 (−16.2, −10.0; P < .001). Significant differences between placebo and d-ATS in the DBP were also observed for the CPRS-R:S and CGI scales (P < .001). Most TEAEs were mild or moderate, with 3 TEAEs (abdominal pain, irritated mood, and appetite loss) leading to study discontinuation in the DOP and none in the DBP. No patients were discontinued due to dermal reactions in either phase.
d-ATS was effective in the treatment of ADHD in children and adolescents, meeting its primary endpoint (reported elsewhere) and all secondary endpoints. d-ATS was safe and well-tolerated, with minimal dermal reactions.
Attention-deficit/hyperactivity disorder (ADHD) is a neurobehavioral disorder characterized by pervasive impairment in symptoms of inattention, hyperactivity, and impulsivity. Psychopharmacologic treatment is targeted at the management of symptoms of ADHD, and evidence exists that ADHD persists into adulthood. Clinical practice guidelines recommend a combination of behavior therapy and psychostimulant medication for the treatment of ADHD in children, adolescents, and adults. Psychostimulants are often prescribed for ADHD in adults, and amphetamine long has been considered a mainstay of treatment for this population. As adult patients seek relief from ADHD symptoms early in the workday and into the early evening hours, with fewer required doses, extended-release formulations with an early onset of efficacy and an extended duration of effect are considered very desirable. The amphetamine-extended release tablet (AMPH ER TAB) was developed to provide a portable, easy-to-use amphetamine tablet dosage option that can be chewed or swallowed whole.
To evaluate the efficacy and safety of an Amphetamine Extended-Release Tablet (AMPH ER TAB) in adults with ADHD aged 18 to 60 years. Methods: In a 5-week forced dose-titration phase, eligible subjects were randomized to either oral double-blind AMPH ER TAB 5 mg starting dose or matching placebo, once daily in the morning beginning the day after the Baseline Visit. Subjects were titrated up (5 mg increments) each week. Safety and efficacy assessments were done weekly. After Visit 3, subjects received 20 mg for 14 (3) days before Visit 5 (V5). Subjects who could not tolerate study drugs discontinued. A Permanent Product Measure of Performance (PERMP) placement test was done at Screening or Baseline. At V5, efficacy assessments included the administration of serial PERMPs predose, 0.5, 1, 2, 4, 8, 10, 12, 13, and 14 hours postdose. The primary efficacy endpoint was the mean PERMP-T score across postdose time points during the Visit 5 serial PERMPs. Safety was monitored by AEs assessed at each visit, C-SSRS, vital signs, weight, and assessment of sleep, appetite, mood, and psychotic AEs.
The mean postdose PERMP-T score over all postdose time points at V5 was statistically significantly higher in the AMPH ER TAB group vs placebo (302.8 vs 279.6; P = .0043). Common adverse events were decreased appetite, insomnia, and dry mouth. The majority of TEAEs were mild to moderate in severity, and no SAEs were reported.
The AMPH ER TAB demonstrated efficacy in the treatment of symptoms of ADHD in adults, with an anticipated safety profile.
Tardive dyskinesia (TD) is a persistent and potentially disabling movement disorder associated with prolonged exposure to antipsychotic medications that jeopardizes adherence to treatment and reduces quality of life. The recognition and management of TD can be challenging in many instances. An online activity was developed to assess the ability of continuing medical education (CME) to improve awareness of the recognition and management of TD among psychiatrists.
The online CME activity consisted of a 30-minute video discussion between three expert faculty. Educational effect was assessed by comparing a matched sample of psychiatrists’ responses to four identical questions pre- and post-activity. A chi-square test identified significant differences between pre- and post-assessment responses. Cramer’s V was used to calculate the effect size of the online education (≥ 0.16 is considerable). Data were collected between June 26 and August 6, 2019.
Activity participation resulted in a considerable educational effect among psychiatrists (n=739; V=0.25, P<0.001). The following areas showed significant (P <0.05) pre- vs post-educational improvements: recognition of incidence of TD associated with different antipsychotic therapies, differentiation of TD from parkinsonism, and the personalized selection of therapies for the management of TD. 37% of psychiatrists had a measurable increase in confidence in understanding the role of the interprofessional team in recognizing TD after activity participation.
The results indicated that a CME-certified 30-minute video activity was effective at improving knowledge among psychiatrists for the recognition and management of TD. Future education should continue to address best practices in the care of patients with TD.
Attention-deficit/hyperactivity disorder (ADHD), the single most common neuropsychiatric disorder with cognitive and behavioral manifestations, often starts in childhood and usually persists into adolescence and adulthood. Rarely seen alone, ADHD is most commonly complicated by other neuropsychiatric disorders that must be factored into any intervention plan to optimally address ADHD symptoms. With more than 30 classical Schedule II (CII) stimulant preparations available for ADHD treatment, only three nonstimulants (atomoxetine and extended-release formulations of clonidine and guanfacine) have been approved by the United States Food and Drug Administration (FDA), all of which focus on modulating the noradrenergic system. Given the heterogeneity and complex nature of ADHD in most patients, research efforts are identifying nonstimulants which modulate pathways beyond the noradrenergic system. New ADHD medications in clinical development include monoamine reuptake inhibitors, monoamine receptor modulators, and multimodal agents that combine receptor agonist/antagonist activity (receptor modulation) and monoamine transporter inhibition. Each of these “pipeline” ADHD medications has a unique chemical structure and differs in its pharmacologic profile in terms of molecular targets and mechanisms. The clinical role for each of these agents will need to be explored with regard to their potential to address the heterogeneity of individuals struggling with ADHD and ADHD-associated comorbidities. This review profiles alternatives to Schedule II (CII) stimulants that are in clinical stages of development (Phase 2 or 3). Particular attention is given to viloxazine extended-release, which has completed Phase 3 studies in children and adolescents with ADHD.
Tardive dyskinesia (TD) is a persistent and potentially disabling movement disorder associated with prolonged antipsychotic use. RE KINECT, a real-world screening study of antipsychotic-treated outpatients, included patients with movements that were clinician-confirmed as possible TD (Cohort 2) and patients with no involuntary movements (Cohort 1). Baseline data from the patient rated EuroQoL 5-Dimension 5-Level questionnaire (EQ-5D-5L) and Sheehan Disability Scale (SDS) were analyzed to evaluate health related quality of life (Cohort 2 vs. Cohort 1) and the effects of possible TD on quality of life (Cohort 2).
Assessments included EQ-5D-5L utility score (0=equivalent to death to 1=perfect health); SDS total score (0=no impact to 30=highest impact); patient- and clinician-rated severity of possible TD in 4 body regions (0=none, 1=some, and 2=a lot; summary score, 0 to 8); and patient-rated impact of possible TD in 7 daily activities (0=none, 1=some, and 2=a lot; summary score, 0 to 14). Populations included Cohort 1 (N=450); full Cohort 2 (N=204); and limited Cohort 2 (N=111, patients who self-reported “some” or “a lot” of TD severity in ≥1 body region). Mean differences between Cohort 2 and Cohort 1 in EQ-5D-5L utility and SDS total scores were analyzed using a generalized linear regression model that was adjusted for potentially confounding factors (e.g., age, sex, psychiatric diagnosis). Associations between TD summary scores (severity, impact) and quality of life (EQ-5D-5L utility, SDS total) were analyzed using a regression model.
The mean score difference between full Cohort 2 (N=204) and Cohort 1 (N=450) was significant for EQ-5D-5L utility (-0.037; P<0.05 [adjusted analysis]) but not SDS total (0.267; P>0.05). However, when limited to Cohort 2 patients who self-reported “a lot” of TD severity (n=53) or impact (n=33), both EQ 5D 5L utility and SDS total scores were significantly worse than in Cohort 1 (P<0.05). Regression coefficients indicated significant associations between patient-rated impact and EQ 5D-5L utility in the full Cohort 2 (-0.021, P<0.001) and limited Cohort 2 (-0.024, P<0.001). A significant association was also found with patient rated severity in limited Cohort 2 (P<0.05), but not with clinician-rated severity. Similar results were found for SDS total score.
RE-KINECT patients were consistent in evaluating the severity and impact of TD, whether based on subjective assessments or standardized patient-reported instruments (EQ-5D-5L, SDS). Clinician-rated severity of TD may not always correlate with patient perceptions of the significance of TD. Patient self-assessments (focused on symptom impact) can be clinically relevant; incorporating such measures into everyday practice may provide a more comprehensive approach to TD assessment and management.
Depression is among the most prevalent mental disorders worldwide, and a substantial proportion of patients do not respond adequately to standard antidepressants. Our understanding of the pathophysiology of depression is no longer limited to the chemical imbalance of neurotransmitters, but also involves the interplay of proinflammatory modulators in the central nervous system, as well as folate metabolism. Additional factors such as stress and metabolic disorders also may contribute. Multiple inflammatory, metabolic, and genetic markers have been identified and may provide critical information to help clinicians individualize treatments for patients to achieve optimal outcomes. Recent advancements in research have clarified underlying causes of depression and have led to possible new avenues for adjunctive treatment. Among these is L-methylfolate, a medical food that is thought to enhance synthesis of monoamines (serotonin, norepinephrine, and dopamine), suppress inflammation, and promote neural health. Clinical studies that assessed supplemental use of L-methylfolate in patients with usual care-resistant depression found that it resulted in improved outcomes. Patients with selective serotonin reuptake inhibitor-resistant depression, and particularly subgroups with biomarkers of inflammation or metabolic disorders or folate metabolism-related genetic polymorphisms (or ≥2 of these factors), had the best responses. Considering this, the goals of this review are to 1) highlight recent advances in the pathophysiology of major depressive disorder as it pertains to folate and associated biomarkers and 2) establish the profiles of patients with depression who could benefit most from supplemental use of L-methylfolate.
The objective of this work was to describe treatment-emergent sexual dysfunction (TESD) and tolerability following a switch from selective serotonin reuptake inhibitor (SSRI: citalopram, paroxetine, or sertraline) monotherapy to vortioxetine or escitalopram monotherapy in adults with well-treated major depressive disorder (MDD) and SSRI-induced sexual dysfunction.
Data were analyzed from the primary study, an 8-week, randomized, double-blind, head-to-head study in which participants with well-treated depressive symptoms but experiencing TESD with SSRIs were directly switched to flexible doses (10/20 mg) of vortioxetine or escitalopram. Sexual functioning was assessed by the Changes in Sexual Functioning Questionnaire-14 (CSFQ-14), efficacy by the Montgomery–Åsberg Depression Rating Scale scores (MADRS) and Clinicians Global Impression of Severity/Improvement (CGI-S/CGI-I), and tolerability by adverse events. Efficacy and tolerability were assessed by pre-switch SSRI therapy where possible, and by participant characteristics.
Greater improvements in TESD were seen in the vortioxetine compared with escitalopram groups based on: participant demographics (≤45 years, women; P = 0.045), prior SSRI treatment (P = 0.044), number of prior major depressive episodes (MDEs) (1–3; P = 0.001), and duration of prior SSRI therapy (>1 year; P = 0.001). Prior SSRI treatment did not appear to influence the incidence or severity of TEAEs, except for nausea. Regardless of prior SSRI, both treatments maintained antidepressant efficacy after 8 weeks.
Results suggest that vortioxetine is a safe and effective switch therapy for treating SSRI-induced sexual dysfunction in adults with well-treated MDD. Also, improvement in sexual dysfunction with vortioxetine or escitalopram may be influenced by prior SSRI usage, sex, age, and history of MDEs.
Buprenorphine (BUP)/samidorphan (SAM) combination is an opioid system modulator being investigated as an adjunctive treatment for major depressive disorder (MDD). BUP/SAM is a fixed-dose combination of BUP, a partial µ-opioid receptor agonist and κ-opioid receptor antagonist, and SAM, a µ-opioid receptor antagonist added to address the abuse and dependence potential of BUP.1,2
We assessed the effects of SAM on the abuse potential of BUP in the BUP/SAM combination in two ways: (1) a human abuse potential (HAP) study in volunteers; and (2) an evaluation of the clinical experience across studies of patients with MDD.
Study 212 (ClinicalTrials.gov ID: NCT02413281) was a HAP study in nondependent, recreational, adult opioid users. Following a qualification period, participants were randomized to 6 treatments in a blinded, crossover design: placebo (PBO), BUP/SAM at the target therapeutic dose (BUP/SAM 2mg/2mg), at 8mg/8mg and 16mg/16mg , and BUP alone (8mg and 16mg). The primary endpoint was maximum effect (Emax) for “At The Moment” Drug Liking Visual Analog Scale (VAS).
The clinical program for BUP/SAM included 4 PBO-controlled studies of patients with MDD (n=961). Pooled safety data were evaluated for adverse events (AEs) that may be associated with abuse, dependence, or withdrawal, as well as for objective signs of withdrawal with the Clinical Opioid Withdrawal Scale (COWS).
In Study 212 (n=38), Emax Drug Liking VAS scores for the BUP/SAM 2mg/2mg dose were similar to those for PBO (median within-subject difference [90% CI]: 2.5 [0.0–9.0]). Emax Drug Liking VAS scores for all BUP/SAM dose groups, including supratherapeutic doses, were significantly lower than those observed for either of the BUP doses. The supratherapeutic doses of BUP/SAM (8mg/8mg and 16mg/16mg) had higher Emax Drug Liking VAS scores than PBO, but the differences were small.
In the MDD controlled studies, the incidence of euphoria-related AEs was low for BUP/SAM 2mg/2mg and PBO (1.6% vs 0.2%, respectively) and there was no evidence of abuse or dependence behavior. Euphoria-related events typically occurred with treatment initiation and resolved with continued treatment. There was minimal evidence of withdrawal by reported AEs or COWS assessment.
These findings indicate that SAM mitigates the abuse potential of BUP in the BUP/SAM combination.
Tardive dyskinesia (TD) is a hyperkinetic movement disorder associated with antipsychotic treatment. RE KINECT (NCT03062033), a real-world study of outpatients prescribed antipsychotics, was designed to identify the presence of possible TD and characterize the impact of involuntary movements on functioning and quality of life. Data from RE-KINECT were used to compare the impact of possible TD in patients with schizophrenia/schizoaffective disorder [SZD] versus mood/other psychiatric disorders [Mood].
Adults with ≥3months of lifetime exposure to antipsychotics and ≥1 psychiatric disorder were recruited. The presence of possible TD was based on clinicians’ observation of involuntary movements in 4 body regions (head, trunk, upper extremities, and lower extremities). Baseline outcomes included demographics, medication history, location/severity of abnormal movements, impact of abnormal movements on daily activities, the Sheehan Disability Scale (SDS), and the EuroQoL 5-Dimensional questionnaire (EQ-5D-5L).
Of 204 patients with clinician-confirmed possible TD, 111 (54.4%) had a SZD diagnosis and 93 (45.6%) had a mood/other psychiatric diagnosis. Significant differences found between groups (Mood vs SZD) included: mean age (56.9 vs 52.7 years; P=0.0263); male sex (33.3% vs 62.2%; P<0.0001); African-American race (7.5% vs 26.1%; P=0.0005); mean lifetime exposure to antipsychotics (9.5 vs 19.5 years; P<0.0001); and percentage of patients currently taking ≥2 psychiatric medications (93.5% vs 79.3%; P=0.0093). Based on clinician observation, there were no significant differences between diagnosis groups in the number of body regions impacted by abnormal movements, maximum severity score across all 4 regions, or patient awareness of possible TD. Over 30% of patients in both groups reported that involuntary movements had “some” or “a lot” of impact on their ability to continue usual activities, be productive, and socialize. No significant differences between the diagnosis groups (Mood vs SZD) were found for mean SDS total score (12.8 vs 10.8), SDS domain scores (work/school [4.1 vs 4.2], social life [4.3 vs 3.7], family life [4.1 vs 3.5]), EQ-5D-5L utility score (0.68 vs 0.74), or EQ-5D-5L health state VAS (64.8 vs 68.5).
In this cohort of outpatients with possible TD, those with Mood disorders were more likely to be older, female, and white than patients with SZD. The ability to function and quality of life were equally impaired in both groups. Further studies on the impact of TD are needed.
Funding Acknowledgements: Neurocrine Biosciences, Inc.
The efficacy of valbenazine (INGREZZA) in tardive dyskinesia (TD) was demonstrated in placebo-controlled clinical trials, based on the Abnormal Involuntary Movement Scale (AIMS) total score (sum of items 1-7). In these trials, mean changes in the AIMS total score were significantly greater with valbenazine 80 mg than with placebo. Currently, no minimal clinically important difference (MCID) has been established for the AIMS total score in patients with TD. Using valbenazine trial data, analyses were conducted to establish a MCID for AIMS total score in TD.
Data were pooled from three 6-week trials: KINECT (NCT01688037), KINECT 2 (NCT01733121), KINECT 3 (NCT02274558). Using the Clinical Global Impression ofChange (CGI-TD) as an anchor comparison, AIMS total score changes from baseline to Week 6 were summarized for all study participants (pooled valbenazine and placebo groups) with a “minimal” CGI-TD score of ≤3 (minimally improved or better) or “robust” ≤2 (much improved or better) at Week 6.
In the pooled population (N=373), 72% and 29% of all participants had CGI-TD scores of ≤3 and ≤2, respectively. The median (maximum, minimum) change from baseline in AIMS total score at Week 6 was -2 (-13, 8) in participants with CGI-TD score ≤3 and -3 ( 13, 8) in participants with a score ≤2.
Pooled data from 3 randomized, double-blind, placebo-controlled trials suggest that a 2 point decrease in AIMS total score may represent the minimal clinically meaningful improvement. Larger AIMS score improvements were associated with “much improved” or “very much improved” CGI TD assessments.
This study was funded by Neurocrine Biosciences, Inc.
Successful treatment of pediatric disorders has necessitated the development of alternative medication formulations, as children may prefer alternative dosage forms to tablets or capsules. This is especially true for attention-deficit/hyperactivity disorder (ADHD), which is one of the most common chronic pediatric conditions and often involves children with a variety of overlapping physical, psychological, or neurodevelopmental disorders. A special challenge for developing alternative dosage forms for ADHD treatment is the incorporation of a once-daily long-acting formulation. Traditional ADHD medication formulations have been limited, and issues surrounding prescribed dosing regimens—including poor medication adherence, difficulty swallowing, and the lack of dosing titration options—persist in ADHD treatment. In other disease areas, the development of alternative formulations has provided options for patients who have issues with consuming solid dosage forms, particularly children and individuals with developmental disorders. In the light of these new developments, several alternative formulations for ADHD medications are under development or have recently become available. This article reviews the various strategies for developing alternative dosage forms in other disease areas and discusses the application of these strategies in ADHD treatment. Alternative dosage forms may increase medication adherence, compliance, and patient preference and, therefore, improve the overall treatment for ADHD.
Aripiprazole lauroxil (AL) is a long-acting injectable atypical antipsychotic that was evaluated for the treatment of schizophrenia in a randomized, placebo-controlled, Phase 3 study. Here, we present exploratory analyses of supportive efficacy endpoints.
Patients experiencing an acute exacerbation of schizophrenia received AL 441 mg intramuscularly (IM), AL 882 mg IM, or matching placebo IM monthly. Supportive endpoints included changes from baseline at subsequent time points in Clinical Global Impression-Severity (CGI-S) scale score; Positive and Negative Syndrome Scale (PANSS) Total score; PANSS Positive, Negative, and General Psychopathology subscale scores; PANSS Marder factors (post hoc); and PANSS responder rate. Overall response rate, based on PANSS Total score and Clinical Global Impression–Improvement (CGI-I) scale score, was also analyzed.
Of 622 patients who were randomized, 596 had ≥1 post-baseline PANSS score. Patients were markedly ill at baseline (mean PANSS Total scores 92–94). Compared with placebo, CGI-S scores; PANSS Positive, Negative, and General Psychopathology subscale scores; and PANSS Marder factors were all significantly (p<0.001) improved by Day 85 with both AL doses, with significantly lower scores starting from Day 8 in most instances. Treatment response rates were significantly (p<0.001) greater with both doses of AL vs placebo.
AL demonstrated robust efficacy on CGI-S score, PANSS subscale scores, PANSS Marder factors, and response rates. Study limitations included use of a fixed dose for initial oral aripiprazole and fixed monthly AL doses without the option to individualize the oral initiation dosing or injection frequency for efficacy, tolerability, or safety.
Cariprazine, a dopamine D3/D2 partial agonist atypical antipsychotic with preferential binding to D3 receptors, is approved for the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder. The efficacy and safety of cariprazine was established in three randomized, double-blind, placebo-controlled, 6-week trials in patients with acute exacerbation of schizophrenia. This 53-week study evaluated the long-term safety and tolerability of cariprazine in patients with schizophrenia.
This was a multicenter, open-label, flexible-dose study of cariprazine 3–9 mg/d in adults with schizophrenia. Participants included new patients and patients who had completed one of two phase III lead-in studies (NCT01104766, NCT01104779). Eligible patients entered a no-drug screening period of up to 1 week followed by 48 weeks of flexibly dosed, open-label cariprazine treatment (3–9 mg/d) and 4 weeks of safety follow-up.
A total of 586 patients received open-label cariprazine treatment, ~39% of whom completed the study. No unexpected safety issues or deaths were reported. The most common (≥10%) adverse events (AEs) observed were akathisia (16%), headache (13%), insomnia (13%), and weight gain (10%). Serious AEs occurred in 59 (10.1%) patients, and 73 (12.5%) patients discontinued the study due to AEs during open-label treatment. Mean changes in metabolic, hepatic, and cardiovascular parameters were not considered clinically relevant. Mean body weight increased by 1.5 kg during the study, prolactin levels decreased slightly, and measures of efficacy remained stable.
Long-term cariprazine treatment at doses up to 9 mg/d appeared to be generally safe and well tolerated in patients with schizophrenia.
Dextromethorphan (DM)/quinidine (Q) is an approved treatment for pseudobulbar affect (PBA) based on trials in amyotrophic lateral sclerosis or multiple sclerosis. PRISM II evaluated DM/Q effectiveness and tolerability for PBA secondary to dementia, stroke, or traumatic brain injury; dementia cohort results are reported.
This was an open-label, multicenter, 90 day trial; patients received DM/Q 20/10 mg twice daily. Primary outcome was change in Center for Neurologic Study–Lability Scale (CNS-LS) score. Secondary outcomes included PBA episode count and Clinical and Patient/Caregiver Global Impression of Change scores with respect to PBA (CGI-C/PGI-C).
134 patients were treated. CNS-LS improved by a mean (SD) of 7.2 (6.0) points at Day 90/Endpoint (P<.001) vs. baseline. PBA episodes were reduced 67.7% (P<.001) vs. baseline; global measures showed 77.5% CGI-C and 76.5% PGI-C “much”/”very much” improved. Adverse events included headache (7.5%), urinary tract infection (4.5%), and diarrhea (3.7%); few patients dropped out for adverse events (10.4%).
DM/Q significantly reduced PBA symptoms in patients with dementia; reported adverse events were consistent with the known safety profile of DM/Q.
Antiepileptic drugs (AEDs) have diverse psychotropic profiles. Some AEDs have proven to be efficacious in the treatment of mood disorders, especially bipolar disorder. Others are ineffective as primary treatments but may be useful adjuncts for mood disorders or comorbid conditions. Valproate (acute mania and mixed episodes), carbamazepine (acute mania and mixed episodes), and lamotrigine (maintenance to delay recurrence) have United States Food and Drug Administration indications for the treatment of bipolar disorder. This article provides an overview of data on the use of AEDs in bipolar disorder, including acute mania and depression, prophylaxis, and rapid cycling.
Objective: Evaluate safety and efficacy of mixed amphetamine salts extended release (MAS XR) in adults with attention-deficit/hyperactivity disorder (ADHD).
Methods: 10-week interim analysis of the Quality of life, Effectiveness, Safety, and Tolerability (QU.E.S.T.) trial, an ongoing, 30-week, open-label, multicenter investigation of once-daily MAS XR (10–60 mg/day) in adults (≥18 years of age) with ADHD in community practice settings.
Findings: With up to 10 weeks of open-label MAS XR 10 to 60 mg/day (final visit mean dose: 37.2 mg/day), 725 adults exhibited rapid, sustained improvement in ADHD symptoms. At end point, significant decreases from baseline were seen in ADHD Rating Scale IV total scores (-19.8±11.6; P<.0001), hyperactivity/impulsivity subscak (-8.1±6.1; P<.0001), and inattentive subscale (-11.6±6.7; P<.0001). Most subjects (74.4%) were rated as very much/much improved. Based on the 36- item Short Form Health Survey (version 2), significant improvements in quality of life were seen in the domains of general health, physical and mental health, vitality, and social, emotional and physical role functioning (P<.0001). Few subjects (6.9%) withdrew due to adverse events; the most common MAS XR-related adverse events were decreased appetite and dry mouth (19.2% each), insomnia (17.8%), and headache (16.8%).
Conclusion: In adults with ADHD, MAS XR treatment is generally safe and demonstrates significant improvement in ADHD symptoms and related quality of life.
Efficacy and safety of aripiprazole administered at doses lower than those previously studied systematically were investigated in patients with acute exacerbation of schizophrenia.
In this double-blind, multicenter study, 367 patients requiring inpatient hospitalization for acute relapse of schizophrenia were randomized to one of three fixed doses of aripiprazole (2, 5, or 10 mg/day) or placebo for 6 weeks. Efficacy and safety parameters were assessed weekly. Primary outcome measure was mean change from baseline in Positive and Negative Syndrome Scale (PANSS)Total score at endpoint.
Aripiprazole 10 mg/day produced statistically significantly greater improvements from baseline compared with placebo for PANSS Total at endpoint (−11.3 vs −5.3; P=.03) and at weeks 2–5. Aripiprazole 5 mg/day did not produce significantly greater improvement in PANSS Total compared with placebo at endpoint, although significant differences were seen at weeks 3–5. No statistically significant improvements compared with placebo were achieved with aripiprazole 2 mg/day at any time points. All aripiprazole doses were well tolerated. Aripiprazole was not associated with significant extrapyramidal symptoms.
While aripiprazole 5 mg/day warrants further study, the 10 mg/day dose provides effective and well-tolerated therapy for management of acute psychosis in patients with schizophrenia.