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The pathophysiology of major depressive disorder (MDD) is thought to result from impaired connectivity between key brain networks. Gamma-aminobutyric acid (GABA) is the key inhibitory neurotransmitter in the brain, working primarily via GABAA receptors, with an important role in virtually all physiologic functions in the brain. Some neuroactive steroids (NASs) are positive allosteric modulators (PAMs) of GABAA receptors and potentiate phasic and tonic inhibitory responses via activation of synaptic and extrasynaptic GABAA receptors, respectively. This review first discusses preclinical and clinical data that support the association of depression with diverse defects in the GABAergic system of neurotransmission. Decreased levels of GABA and NASs have been observed in adults with depression compared with healthy controls, while treatment with antidepressants normalized the altered levels of GABA and NASs. Second, as there has been intense interest in treatment approaches for depression that target dysregulated GABAergic neurotransmission, we discuss NASs approved or currently in clinical development for the treatment of depression. Brexanolone, an intravenous NAS and a GABAA receptor PAM, is approved by the U.S. Food and Drug Administration for the treatment of postpartum depression (PPD) in patients 15 years and older. Other NASs include zuranolone, an investigational oral GABAA receptor PAM, and PH10, which acts on nasal chemosensory receptors; clinical data to date have shown improvement in depressive symptoms with these investigational NASs in adults with MDD or PPD. Finally, the review discusses how NAS GABAA receptor PAMs may potentially address the unmet need for novel and effective treatments with rapid and sustained antidepressant effects in patients with MDD.

SPN-812 (viloxazine extended-release) is under investigation for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents. This Phase III study evaluated the efficacy and tolerability of SPN-812 200 and 400 mg once daily in children 6–11 years of age with ADHD. Patients were randomly assigned to receive SPN-812 200 mg, SPN-812 400 mg, or placebo, once daily for 8 weeks (including ≤3 weeks titration period). The primary efficacy endpoint was the change from baseline (CFB) in ADHD Rating Scale (RS)-5 Total score at end of study (EOS). Key secondary endpoints included Clinical Global Impression–Improvement (CGI-I) score at EOS, CFB in Conners 3–Parent Short Form (PS) composite T-score at EOS, and CFB in Weiss Functional Impairment Rating Scale–Parent (WFIRS-P) Total average score at EOS. A total of 313 patients were enrolled, with 301 in the intent-to-treat population (194 boys, 107 girls; mean age [SD], 8.4 [1.7] years). At EOS, the CFBs in ADHD-RS-5 Total score and CGI-I score were significantly improved with both 200- and 400-mg/d SPN-812 versus placebo (ADHD-RS-5, P = 0.0038 and 0.0063, respectively; CGI-I, P = 0.0028 and 0.0099). At EOS, the CFB in Conners 3-PS composite T-score was significantly improved with 200- (P = 0.0064), but not 400-mg/d (P = 0.0917), SPN-812 compared to placebo. No significant difference between the groups was found in WFIRS-P Total average score. The rate of discontinuations due to adverse events in both SPN-812 treatment groups combined was <5%. SPN-812 200 and 400 mg once daily was associated with improvements in ADHD symptoms in school-aged children and was generally well tolerated. ClinicalTrials.gov identifier: NCT03247543. •SPN-812 (viloxazine extended-release) is a nonstimulant under development for ADHD.•Once-daily 200- and 400-mg SPN-812 improved ADHD-RS-5 and CGI-I scores vs. placebo.•SPN-812 was well tolerated with low rates of discontinuations due to adverse events.•Another Phase 3 trial demonstrated efficacy and safety of 100- and 200-mg SPN-812.

Background Anhedonia is a core feature of major depressive disorder (MDD), yet the clinical burden in real-world settings is not well understood. This retrospective cohort study assessed depression symptoms and treatment patterns among patients with MDD with and without prominent anhedonia. Methods Patients with MDD were selected from a real-world dataset of electronic health records from mental health specialists and linked medical and pharmacy claims (OM1, Inc. Boston MA) between January 2013 through August 2023. Patients were included if the first Patient Health Questionnaire 9-item (PHQ-9) score indicated moderate to severe depression (≥ 10) with a MDD diagnosis +/-30 days. The date of the patients’ first PHQ-9 score was used as the index date. Patients with a score ≥ 2 on PHQ-9 item 1 (anhedonia) at the index date were classified as MDD with prominent anhedonia (MDD-ANH) ( n  = 4,255). The remaining patients were classified as Other-MDD ( n  = 1,454). Treatment patterns were assessed using prescription records in the year following the index date. The last PHQ-9 score in the year following the index date was used to assess remission rates (PHQ-9 score < 5) or persistence of moderate to severe depression. Results A total of 5,709 patients with MDD were assessed; 74.5% were in MDD-ANH and 25.5% were in the Other-MDD cohort (met criteria for MDD but not prominent anhedonia). The mean index PHQ-9 score was 18.2 (SD = 4.2) for MDD-ANH patients and 13.5 (SD = 2.9) for Other-MDD patients. The percentage of patients treated with antidepressants was 86.4% in the MDD-ANH group and 84.7% in the Other-MDD group. After adjusting for baseline characteristics, patients with MDD-ANH were more likely to have been treated with atypical antipsychotics (OR = 1.51, p  < 0.001), more likely to have switched medication (OR = 1.24, p  = 0.004), and more likely to have augmented antidepressant therapy (OR = 1.16, p  = 0.021) than Other-MDD patients. Patients with MDD-ANH were less likely to have achieved remission (OR = 0.82, p  = 0.003) and were more likely to have persistent depression (OR = 1.50, p  < 0.001) than patients with Other-MDD. Conclusions Overall, MDD-ANH patients had higher clinical burden reflected in more depressive symptoms, higher treatment utilization and lower rates of remission compared to Other-MDD.

•Observed weight gain with cariprazine was less than 1.5 kg up to a year of follow-up.•Changes in other metabolic parameters (HbA1c, HDL, LDL) were small with cariprazine.•Most patients with high baseline cholesterol/triglycerides shifted to normal range.•Most patients with normal baseline cholesterol/triglycerides remained normal. Weight gain and associated negative cardiometabolic effects can occur as a result of mental illness or treatment with second-generation antipsychotics (SGAs), leading to increased rates of morbidity and mortality. In this analysis, we evaluated the effect of the SGA cariprazine on weight and metabolic parameters in a real-world, retrospective, observational dataset. Electronic health records from the Optum Humedica database (October 1, 2014–December 31, 2020) were analyzed during the 12-month period before starting cariprazine (baseline) and for up to 12 months following cariprazine initiation; approved and off-label indications were included. Body weight trajectories were estimated in the overall patient cohort and at 3-, 6-, and 12-month timepoints (primary objective). Changes in hemoglobin A1c (HbA1c), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides were also evaluated (secondary objectives). Percentages of patients with clinically relevant shifts in body weight, total cholesterol, and fasting triglycerides were also determined. Discontinuation rates for metabolic regulating medications were calculated. Average predicted values were estimated by linear mixed-effects regression models. A total of 2,301 patients were included; average duration of follow-up was 133.7 days. Average predicted weight change for patients during the cariprazine overall follow-up period was +2.4 kg, with predicted weight changes of +0.8 kg (n = 811), +1.1 kg (n = 350), and +1.4 kg (n = 107) at months 3, 6, and 12, respectively. Overall, the majority of patients did not experience clinically significant (≥7%) weight gain (82.8%) or loss (90.5%) after starting cariprazine. Average predicted HbA1c levels (n = 189) increased during baseline (0.15%/year) and decreased during cariprazine treatment (−0.2%/year). Average predicted triglyceride levels (n = 257) increased during baseline (15.0 mg/dL/year) and decreased during cariprazine treatment (−0.7 mg/dL/year). Predicted LDL (n = 247) and HDL (n = 255) values decreased during baseline (−7.3 and −1.1 mg/dL/year, respectively); during cariprazine treatment, LDL increased by 5.6 mg/dL/year and HDL decreased by −0.6 mg/dL/year. During follow-up, most patients did not shift from normal/borderline to high total cholesterol (<240 to ≥240 mg/dL; 522 [90.2%]) or fasting triglyceride (<200 to ≥200 mg/dL; 143 [88.8%] patients) levels; shifts from high to normal/borderline levels occurred in 44 (61.1%) patients for total cholesterol and 38 (57.6%) patients for fasting triglycerides. After starting cariprazine, the discontinuation rate per 100 patient-years was 60.4 for antihyperglycemic medication and 87.4 for hyperlipidemia medication. These real-world results support short-term clinical trial findings describing a neutral weight and metabolic profile associated with cariprazine treatment and they expand the dataset to include long-term follow-up.

Background Schizophrenia is a chronic and debilitating neuropsychiatric disorder that often requires long-term pharmacotherapy to manage symptoms and prevent relapse. Cariprazine is a potent dopamine D 3 and D 2 receptor partial agonist that is FDA-approved in the US for the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder in adults; the recommended dose range is 1.5–6 mg/d. Methods To further characterize the long-term safety of cariprazine, data from two 48-week open-label, flexible-dose extension studies were pooled for post hoc analyses. Outcomes were evaluated in the pooled safety population (patients who received ≥1 dose of cariprazine during an open-label extension period); findings were summarized using descriptive statistics for the overall cariprazine group and in modal daily dose groups (1.5–3, 4.5–6, and 9 mg/d). Results Of the 679 patients in the overall cariprazine safety population, 40.1% completed the study. The only adverse events (AEs) leading to discontinuation of ≥2% of patients in any dose group were akathisia, worsening of schizophrenia, and psychotic disorder. Treatment-emergent AEs (TEAEs) of akathisia, insomnia, weight increased, and headache were reported in ≥10% of the overall population. Mean prolactin levels decreased in all dose groups (overall, −15.4 ng/mL). Clinically insignificant changes in aminotransferase levels and alkaline phosphatase were observed; no dose-response relationship was observed across groups. Mean total (−5.3 mg/dL), low-density lipoprotein (−3.5 mg/dL), and high-density lipoprotein (−0.8 mg/dL) cholesterol levels decreased; no dose-response relationship was observed for metabolic parameters. Mean change in body weight was 1.58 kg; body weight increase and decrease ≥7% occurred in 27% and 11% of patients, respectively. Mean changes in cardiovascular parameters, including blood pressure and pulse, were generally not considered clinically significant. EPS-related TEAEs that occurred in ≥5% of patients were akathisia, tremor, restlessness, and extrapyramidal disorder. Conclusion In these post hoc pooled analyses of data from 2 long-term open-label studies, treatment with cariprazine was generally safe and well tolerated. Results support the safety and tolerability of cariprazine within the FDA-recommended dose range of 1.5–6 mg/d for schizophrenia. Clinical trials registration NCT01104792, NCT00839852.

Background Atypical antipsychotics are a common treatment for serious mental illness, but many are associated with adverse effects, including weight gain and cardiovascular issues, and real-world experience may differ from clinical trial data. Cariprazine has previously demonstrated a favorable safety and tolerability profile in clinical trials. Here, we evaluated the effects of cariprazine on body weight and blood pressure for bipolar I disorder (BP-I), schizophrenia, or as adjunctive treatment for major depressive disorder (MDD) using real-world data. Methods Symphony Health’s Integrated Dataverse® with electronic medical record access (3/1/2015–10/31/2018) was used to identify adults (≥ 18 years) diagnosed with BP-I depression, BP-I mania/mixed, schizophrenia, or MDD, with ≥ 2 cariprazine dispensings (first dispensing = index) and continuous clinical activity for ≥ 12 months pre-index (baseline) and ≥ 3 months post-index. The on-treatment period spanned from index to cariprazine discontinuation, exposure to another atypical or long-acting injectable antipsychotic, or end of clinical activity/data availability. Outcomes included estimated annual linear trajectories for weight, body mass index (BMI), systolic blood pressure (SBP), and diastolic blood pressure (DBP) during baseline and on treatment. Changes were estimated using linear mixed-effects models fitted over measurements pre-index and on treatment; 95% CIs were derived from nonparametric bootstrap procedures. Results The body weight analysis included 612 patients (BP-I, n = 331 [BP-I depression, n = 172; BP-I mania/mixed, n = 159]; schizophrenia, n = 75; MDD, n = 206). The mean patient age was 43.4 years, 75.2% were female, and the mean (SD) on-treatment period was 219 (185) days. Among patients with measurements before and during cariprazine treatment, estimated annual weight trajectories were + 3.55 (95% CI 2.38, 4.59) kg/year before cariprazine initiation and + 0.91 (− 1.17, 2.82) kg/year during cariprazine treatment. Additionally, annual linear trajectories evaluated across the on-treatment period were + 0.31 (− 0.42, 1.01) kg/m 2 /year for BMI, − 2.38 (− 4.27, − 0.76) mmHg/year for SBP, and − 0.57 (− 1.75, 0.61) mmHg/year for DBP. Conclusion In this real-world analysis, cariprazine was associated with an estimated weight gain of + 0.91 kg/year and had minimal impact on BMI and blood pressure when evaluated up to 12 months.

Attention-deficit/hyperactivity disorder (ADHD) is a highly heterogeneous disorder for which treatment personalization is essential. Stimulant medications are the first-line option for ADHD management due to their high efficacy. While the choice of stimulant is limited to methylphenidate or amphetamine, there are numerous formulation options each associated with different potential benefits and restrictions. The goal is to deliver a stimulant medication that provides an even, continuous control of symptoms tailored to the patient’s symptoms and lifestyle. This article reviews the technologies used to deliver stimulants and the impact their characteristics have on the pharmacokinetic profiles, dosing regimens, and flexibility of the medication. The aim was to help clinicians in their treatment decision-making process and provide patients with effective and individualized management of their ADHD symptoms.

Abstract Background Tardive dyskinesia (TD) is a persistent and potentially disabling movement disorder associated with antipsychotic use. Data from RE-KINECT, a real-world study of antipsychotic-treated outpatients, were analyzed to assess the effects of possible TD on patient health and social functioning. Methods Analyses were conducted in Cohort 1 (patients with no abnormal involuntary movements) and Cohort 2 (patients with possible TD per clinician judgment). Assessments included: EuroQoL’s EQ-5D-5L utility (health); Sheehan Disability Scale (SDS) total score (social functioning); patient- and clinician-rated severity of possible TD (“none”, “some”, “a lot”); and patient-rated impact of possible TD (“none”, “some”, “a lot”). Regression models were used to analyze the following: associations between higher (worse) severity/impact scores and lower (worse) EQ-5D-5L utility (indicated by negative regression coefficients); and associations between higher (worse) severity/impact scores and higher (worse) SDS total score (indicated by positive regression coefficients). Results In Cohort 2 patients who were aware of their abnormal movements, patient-rated TD impact was highly and significantly associated with EQ-5D-5L utility (regression coefficient: − 0.023, P  < 0.001) and SDS total score (1.027, P  < 0.001). Patient-rated severity was also significantly associated with EQ-5D-5L utility (− 0.028, P  < 0.05). Clinician-rated severity was moderately associated with both EQ-5D-5L and SDS, but these associations were not statistically significant. Conclusions Patients were consistent in evaluating the impacts of possible TD on their lives, whether based on subjective ratings (“none”, “some”, “a lot”) or standardized instruments (EQ-5D-5L, SDS). Clinician-rated severity of TD may not always correlate with patient perceptions of the significance of TD.

Abstract Background Schizophrenia is a disabling disorder that profoundly affects functioning and quality of life. While available antipsychotics have improved outcomes for patients with schizophrenia, they are relatively ineffective for negative and cognitive symptoms and are associated with a range of troublesome side effects. A significant unmet medical need for more effective and better-tolerated therapies remains. Methods A roundtable consisting of 4 experts in the treatment of patients with schizophrenia convened to discuss the current treatment landscape, unmet needs from patient and societal perspectives, and the potential of emerging therapies with novel mechanisms of action (MOAs). Results Key areas of unmet need include optimal implementation of available treatments, effective treatment of negative and cognitive symptoms, improvements in medication adherence, novel MOAs, avoidance of postsynaptic dopamine blockade–related adverse effects, and individualized approaches to treatment. With the possible exception of clozapine, all currently available antipsychotics primarily act by blocking dopamine D2 receptors. Agents with novel MOAs are urgently needed to effectively target the full range of symptoms in schizophrenia and facilitate an individualized treatment approach. Discussion focused on promising novel MOAs that have demonstrated potential in phase 2 and 3 trials include muscarinic receptor agonism, trace amine-associated receptor 1 agonism, serotonin receptor antagonism/inverse agonism, and glutamatergic modulation. Conclusions Results from early clinical trials of agents with novel MOAs are encouraging, particularly for muscarinic and trace amine-associated receptor 1 agonists. These agents offer renewed hope for meaningful improvement in the management of patients with schizophrenia.

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.