Once-daily dosing with dasotraline, a novel dopamine and norepinephrine reuptake inhibitor, achieves stable plasma concentrations over 24 hours. This phase 3 study evaluated the efficacy and safety of dasotraline in children with attention deficithyperactivity disorder (ADHD) throughout the day, in a laboratory classroom setting (NCT02734693).

Children (6–12 years) meeting DSM-5 criteria for ADHD were randomized to 2 weeks of dasotraline or placebo (dosed daily at home at approximately 8 PM). Following an abbreviated practice day, laboratory classroom evaluations took place at baseline and on Day 15. The primary endpoint was mean change from baseline at Day 15 in ADHD symptoms, as measured by the Swanson, Kotkin, Agler, M-Flynn, and Pelham Combined Score (SKAMP-CS), obtained from the average of 7 assessments collected across the 12-hour laboratory classroom day (12–24 hours post-dose). Secondary endpoints included SKAMP scores obtained throughout the day at individual timepoints from 8 AM through 8 PM (12–24 hours post-dose), and measures of safety and tolerability.

The ITT population comprised 112 patients. Mean age was 9.5 years, 68.8% were male; 92% completed the study. Dasotraline 4 mg/day significantly improved mean SKAMP-CS versus placebo (p<0.0001, effect size 0.85) with significant effects persisting throughout the day. Mean SKAMP subscores improved significantly versus placebo (Attention p<0.0001, effect size 0.81; Deportment p<0.001, effect size 0.70). Treatment-emergent adverse events were generally mild or moderate in severity; most frequent (with dasotraline 4 mg/day; placebo) included: insomnia (19.6%; 3.6%, all terms combined), decreased appetite (10.7%; 3.6%), headache (10.7%; 8.9%), affect lability (8.9%; 7.1%), irritability (5.4%; 3.6%), postural orthostatic tachycardia syndrome (5.4%; 0%), and perceptual disturbances (5.4%; 0%).

In this 2-week, randomized, double-blind, laboratory classroom study in children with ADHD, once-daily dasotraline significantly improved ADHD symptoms (including deportment and attention), compared with placebo, and demonstrated sustained efficacyup to 24 hours post-dose. The most common adverse events were insomnia, decreased appetite, and headache.

Study sponsored by Sunovion Pharmaceuticals Inc.

Insomnia was associated with cerebral structural changes and Alzheimer’s disease. However, associations among cerebral perfusion, insomnia with cerebral small vessel disease (CSVD), and cognitive performance were little investigated.

This cross-sectional study included 89 patients with CSVDs and white matter hyperintensities (WMHs). They were dichotomized into the normal sleep and poor sleep group, according to Pittsburgh sleep quality index (PSQI). Baseline characteristics, cognitive performance, and cerebral blood flow (CBF) were measured and compared between the two groups. The association or correlation between cerebral perfusion, cognition, and insomnia was analyzed using binary logistic regression.

Our study found that declined MoCA score (P = .0317) was more prevalent in those with poor sleep. There was a statistical difference in the recall (P = .0342) of MMSE, the delayed recall (P = .0289) of MoCA between the two groups. Logistic regression analysis showed educational background (P < .001) and insomnia severity index (ISI) score (P = .039) were independently correlated with MoCA scores. Arterial spin labeling demonstrated that left hippocampal gray matter perfusion was significantly reduced (P = .0384) in the group with poor sleep. And, negative correlation was found between left hippocampal perfusion and PSQI scores.

In the patients with CSVDs, insomnia severity was associated with cognitive decline. Left hippocampal gray matter perfusion was correlated with PSQI scores in CSVDs.

Demand for digital mental health tools has risen since the start of the COVID-19 pandemic; however, their evolving use in mental health care is not well understood. We surveyed mental health care professionals (HCPs) before and after the onset of the pandemic and assessed how use of and attitudes about digital technology changed.

We distributed a digital health survey to HCPs in the United States in 2019 (pre-pandemic; N = 141) and in 2021 (during the pandemic; N = 151). Both surveys recorded the respondents’ perceived barriers to integrating new digital health technologies and the tools they currently used in their practice.

HCP use of telemedicine increased from 47% of respondents in 2019 to 81% in 2021, as did the use of mHealth sensors (2% vs 10%). Patient comfort with technology remained one of the biggest barriers to implementing new digital tools (40% vs 43%), while difficulty integrating digital tools into clinical practice became less common (40% vs 32%). Data management (19% vs 10%) and patient acceptability (19% vs 13%) were cited less often as barriers in 2021. Respondents’ thoughts on what can be most improved by digital technology shifted substantially, with increased access to care rising from 27% of responses in 2019 to 46% in 2021.

The pandemic has changed how HCPs perceive digital health technologies and how they implement these tools in clinical practice. A growing number of HCPs believe increased access to care is the outcome that technology can most improve.

Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, USA

Treatments for MDD that can improve both overall depressive and anhedonic symptoms are urgently needed.

AXS-05 (dextromethorphan-bupropion) is a novel, oral, investigational NMDA receptor antagonist with multimodal activity being developed for MDD. The dextromethorphan component of AXS-05 is an NMDA receptor antagonist and a sigma-1 receptor agonist. The bupropion component of AXS-05 serves primarily to increase the bioavailability of dextromethorphan.

To evaluate the effect of AXS-05 in improving anhedonic symptoms in MDD.

GEMINI (N=327) was a randomized, double-blind, placebo-controlled, 6-week study, which randomized adults with MDD to AXS-05 (dextromethorphan HBr 45 mg- bupropion HCl 105 mg) or placebo, twice daily. The primary endpoint was change from baseline in the MADRS total score at Week 6. A post-hoc analysis was conducted to determine the impact of AXS-05 versus placebo on the 5-item MADRS anhedonia subscale (MAS).

Baseline MAS scores were 19.8 and 19.6 in the AXS-05 and placebo group, respectively. At Week 1, AXS-05 treatment resulted in a significant mean reduction from baseline in the MAS score of 4.44 versus 2.69 points for placebo (p< 0.001). At Week 6, the mean reduction from baseline in the MAS was 9.70 for AXS-05 compared to 7.22 for placebo (p=0.001). Response rates (≥ 50% MAS improvement) were significantly greater for AXS-05 compared to placebo at Week 1 (p< 0.001) and at every time point thereafter.

Treatment with AXS-05 was generally safe and well tolerated. The most common adverse events being dizziness, nausea, headache, diarrhea, somnolence, and dry mouth.

Treatment with AXS-05 rapidly and significantly reduced anhedonic symptoms as well as overall depressive symptoms.

Axsome Therapeutics

To examine the effect of esketamine nasal spray (ESK) plus newly initiated oral antidepressant (OAD) versus OAD plus placebo nasal spray (PBO) on the association between Montgomery–Åsberg Depression Rating Scale (MADRS) and 9-item Patient Health Questionnaire (PHQ-9) scores in adults with treatment-resistant depression (TRD).

Data from TRANSFORM-1 and TRANSFORM-2 (two similarly designed, randomized, active-controlled TRD studies) and SUSTAIN-1 (relapse prevention study) were analyzed. Group differences for mean changes in PHQ-9 total score from baseline were compared using analysis of covariance. Associations between MADRS and PHQ-9 total scores from TRANSFORM-1/TRANSFORM-2 were assessed using simple parametric, nonparametric, and multiple regression models.

In TRANSFORM-1/TRANSFORM-2 (ESK + OAD, n = 343; OAD + PBO, n = 222), baseline PHQ-9 mean scores were 20.4 for ESK + OAD and 20.6 for OAD + PBO (severe depression). At day 28, significant group differences were observed in least squares mean change (SE) in PHQ-9 scores from baseline (−12.8 [0.46] vs −10.3 [0.53], P < .001) and in clinically substantial change in PHQ-9 scores (≥6 points; 77.1% vs 64%, P < .001) in ESK + OAD and OAD + PBO groups, respectively. A nonlinear relationship between MADRS and PHQ-9 was observed; total scores demonstrated increased correlation over time. In SUSTAIN-1, 57.3% of patients receiving ESK + OAD (n = 89) versus 44.2% receiving OAD + PBO (n = 86) retained remission status (PHQ-9 score ≤4) at maintenance treatment end point (P = .044).

In adults with TRD, ESK + OAD significantly improved severity of depressive symptoms, and more patients achieved clinically meaningful changes in depressive symptoms based on PHQ-9, versus OAD + PBO. PHQ-9 outcomes were consistent with those of clinician-rated MADRS.

ClinicalTrials.gov: NCT02417064, NCT02418585, NCT02493868.

Chorea is defined as a hyperactive movement disorder associated with involuntary, quick, and unpredictable muscle contractions of the limbs, face, and trunk. The unpredictable nature of these movements includes variation in speed, timing, and direction of movement. A wide variety of medications, medical conditions and illicit drugs have been associated with movement disorders. Examples include a multitude of antipsychotic induced movement disorders and dyskinesia related to dopaminergic agents, like levodopa and metoclopramide. Dyskinesias have been associated with psycho-stimulant use, such as methylphenidate. However, most cases reported were associated with large doses or chronic use. Aside from dyskinesia, methylphenidate is known to be associated with tic disorder, tremor, and muscle spasm. However, this case reported is unlike any of the above described and involved the development of chorea after only 2 days of moderate doses of methylphenidate, in a patient on chronic methadone maintenance treatment, with successful arrest of symptoms following discontinuation of the methylphenidate.

A 47-year-old female was admitted to our hospital after presenting to the emergency department with 1 week of violent flailing movements. The ballistic flailing movements started acutely after 2 days of initiating methylphenidate in addition to her chronic methadone treatment and 2-week period of initiation of paroxetine. Lab work showed normal CBC, CMP, CRP, CK, and TSH. Urine drug screen, CT angiography of the head, and Huntington’s disease testing were all unremarkable, suggesting a decreased likelihood of illicit drugs, traumatic brain injury, or Huntington’s disease etiologies. Confirmation of the diagnosis was made as the chorea symptoms abruptly resolved upon discontinuation of methylphenidate and administration of intravenous Benadryl. The patient has been on methadone alone for 11 months and methylphenidate alone 2 years back with no involuntary movements or any similar presentation that shows the possibility of drug interaction through cytochrome P450 metabolism between Methylphenidate and methadone.

We are presenting a rare case report that adds on to the scarce literature on methylphenidate-induced chorea. It also challenges the consulting psychiatrists to broaden their differential diagnosis for acute onset of choreiform movement disorders. This unique case intrigues the thought process to consider the interaction of methylphenidate in the presence of cytochrome P450 2D6 and 3A4 inhibitors like methadone.

Evidence has suggested that emotional dysregulation is a transdiagnostic feature in schizophrenia and major affective disorders. However, the relationship between emotional dysregulation and appetite hormone disturbance remains unknown in nonobese adolescents with first-episode schizophrenia, bipolar disorder, and major depressive disorder.

In total, 22 adolescents with schizophrenia; 31 with bipolar disorder; 33 with major depressive disorder; and 41 healthy age-, sex-, and body mass index (BMI)/BMI percentile-matched controls were enrolled for assessing levels of appetite hormones, namely leptin, ghrelin, insulin, and adiponectin. Emotional regulation symptoms were measured using the parent-reported Child Behavior Checklist―Dysregulation Profile.

Adolescents with first-episode schizophrenia, bipolar disorder, and major depressive disorder exhibited greater emotional dysregulation symptoms than the control group (P = .037). Adolescents with bipolar disorder demonstrated higher log-transformed levels of insulin (P = .029) and lower log-transformed levels of leptin (P = .018) compared with the control group. BMI (P < .05) and log-transformed ghrelin levels (P = .028) were positively correlated with emotional dysregulation symptoms.

Emotional dysregulation and appetite hormone disturbance may occur in the early stage of severe mental disorders. Further studies are required to clarify the unidirectional or bidirectional association of emotional dysregulation with BMI/BMI percentile and appetite hormones among patients with severe mental disorder.

The Montgomery-Åsberg Depression Rating Scale (MADRS) is commonly used for the assessment of depressive symptom changes in patients with major depressive disorder (MDD) or bipolar depression. Categories of depression severity that correspond to ranges of MADRS total score have been previously reported in patients with MDD, but it appears that MADRS severity ranges have not been reported for patients with bipolar I disorder. The objective of this study was to evaluate MADRS total score ranges that correspond with different grades of depression severity in patients with bipolar I depression.

Data were pooled from 3 randomized, double-blind, placebo-controlled, 6- or 8-week trials of cariprazine in patients with bipolar I depression. MADRS severity ranges were evaluated using an anchor-based approach with the clinician-rated, 7-category Clinical Global Impression-Severity (CGI-S) scale. CGI-S has previously been used to determine severity thresholds in MDD. Correlations between MADRS total score and CGI-S score were assessed in the pooled dataset at week 6; placebo and active treatment arms were pooled together. Youden index from receiver operating characteristic (ROC) curves was used to determine the optimal threshold for MADRS total score corresponding to each CGI-S severity level.

The pooled dataset included 1523 patients with bipolar depression. Mean CGI-S scores were highly correlated with mean MADRS total scores at week 6 (r=.87; P<.0001), with MADRS total scores increasing with CGI-S severity. Using the ROC curves, MADRS total score ranges corresponding to each CGI-S severity category were estimated as follows: score of 0-6 for “normal, not at all ill”, 7-12 for “borderline mentally ill”, 13-18 for “mildly ill”, 19-23 for “moderately ill”, 24-36 for “markedly ill”, 37-39 for “severely ill”, and 40 or greater for “extremely ill”. Area under the curve (AUC) values for these cutoffs ranged from 0.930 to 0.997, representing outstanding sensitivity and specificity.

Utilizing data from 3 recent clinical trials of subjects with bipolar depression, we were able to identify MADRS severity thresholds. These empirical findings may help clinicians to understand and contextualize MADRS results from bipolar clinical research and apply to their patients in practice.

AbbVie Inc.