Overview of Psychiatric Medications in the Pipeline in Phase III Trials as of June 1, 2024: A Systematic Review.

Objective: This systematic review provides an overview of psychiatric medications in the late stages of development (Phase III clinical trials) as of June 1, 2024. It details the mechanisms of action, efficacy, dosing, and adverse effects of these medications. Methods: We searched the PubMed database for Phase III studies of psychiatric medications published until June 1, 2024, using the keywords "psychiatric" OR "psychopharm*" AND "medic*" OR "pharm*". Our review encompassed medications currently undergoing Phase III clinical trials and those that have completed Phase III but are awaiting approval from the United States Food and Drug Administration (FDA). We independently analyzed the identified studies and reached a consensus on the medications to be included in this systematic review. Results: As of June 1, 2024, a total of 89 pipeline drug trials were identified, including nine for schizophrenia, five for bipolar disorders, 25 for depressive disorders, 11 for anxiety disorders, five for post-traumatic stress disorder (PTSD), one for obsessive compulsive disorder (OCD), two for eating disorders, two for sleep-wake disorders, three for sexual dysfunctions, one for substance-related and addictive disorders, 22 for neurocognitive disorders, and three for neurodevelopmental disorders, specifically attention deficit hyperactivity disorder (ADHD). Conclusion: The psychiatric medications in the pipeline as of June 1, 2024, demonstrate significant promise in treating psychiatric disorders.

Characterization of a rhabdomyosarcoma reveals a critical role for SMG7 in cancer cell viability and tumor growth.

Soft-tissue sarcomas (STSs) are a rare and diverse group of mesenchymal cancers plagued with aggression, poor response to systemic therapy, and high rates of recurrence. Although STSs generally have low mutational burdens, the most commonly mutated genes are tumor suppressors, which frequently acquire mutations inducing nonsense-mediated mRNA decay (NMD). This suggests that STS cells may exploit NMD to suppress these anti-cancer genes. To examine the role that the NMD factor SMG7 plays in STS, we developed an inducible knockout mouse model in the Trp53-/- background. Here, we isolated a subcutaneous STS and identified it as a rhabdomyosarcoma (RMS). We report that knockout of SMG7 significantly inhibited NMD in our RMS cells, which led to the induction of NMD targets GADD45b and the tumor suppressor GAS5. The loss of NMD and upregulation of these anti-cancer genes were concomitant with the loss of RMS cell viability and inhibited tumor growth. Importantly, SMG7 was dispensable for homeostasis in our mouse embryonic fibroblasts and adult mice. Overall, our data show that the loss of SMG7 induces a strong anti-cancer effect both in vitro and in vivo. We present here the first evidence that disrupting SMG7 function may be tolerable and provide a therapeutic benefit for STS treatment.

Identification and characterization of a set of monocot BAHD monolignol transferases.

Plant BAHD acyltransferases perform a wide range of enzymatic tasks in primary and secondary metabolism. Acyl-CoA monolignol transferases, which couple a CoA substrate to a monolignol creating an ester linkage, represent a more recent class of such acyltransferases. The resulting conjugates may be used for plant defense but are also deployed as important "monomers" for lignification, in which they are incorporated into the growing lignin polymer chain. p-Coumaroyl-CoA monolignol transferases (PMTs) increase the production of monolignol p-coumarates, and feruloyl-CoA monolignol transferases (FMTs) catalyze the production of monolignol ferulate conjugates. We identified putative FMT and PMT enzymes in sorghum (Sorghum bicolor) and switchgrass (Panicum virgatum) and have compared their activities to those of known monolignol transferases. The putative FMT enzymes produced both monolignol ferulate and monolignol p-coumarate conjugates, whereas the putative PMT enzymes produced monolignol p-coumarate conjugates. Enzyme activity measurements revealed that the putative FMT enzymes are not as efficient as the rice (Oryza sativa) control OsFMT enzyme under the conditions tested, but the SbPMT enzyme is as active as the control OsPMT enzyme. These putative FMTs and PMTs were transformed into Arabidopsis (Arabidopsis thaliana) to test their activities and abilities to biosynthesize monolignol conjugates for lignification in planta. The presence of ferulates and p-coumarates on the lignin of these transformants indicated that the putative FMTs and PMTs act as functional feruloyl-CoA and p-coumaroyl-CoA monolignol transferases within plants.

Enhancing photosynthetic production of glycogen-rich biomass for use as a fermentation feedstock.

Current sources of fermentation feedstocks, i.e. corn, sugar cane, or plant biomass, fall short of demand for liquid transportation fuels and commodity chemicals in the United States. Aquatic phototrophs including cyanobacteria have the potential to supplement the supply of current fermentable feedstocks. In this strategy, cells are engineered to accumulate storage molecules including glycogen, cellulose, and/or lipid oils that can be extracted from harvested biomass and fed to heterotrophic organisms engineered to produce desired chemical products. In this manuscript, we examine the production of glycogen in the model cyanobacteria, Synechococcus sp. strain PCC 7002, and subsequent conversion of cyanobacterial biomass by an engineered Escherichia coli to octanoic acid as a model product. In effort to maximize glycogen production, we explored the deletion of catabolic enzymes and overexpression of GlgC, an enzyme that catalyzes the first committed step towards glycogen synthesis. We found that deletion of glgP increased final glycogen titers when cells were grown in diurnal light. Overexpression of GlgC led to a temporal increase in glycogen content but not in an overall increase in final titer or content. The best strains were grown, harvested, and used to formulate media for growth of E. coli. The cyanobacterial media was able to support the growth of an engineered E. coli and produce octanoic acid at the same titer as common laboratory media.

Major Depression Comorbid with Medical Conditions: Analysis of Quality of Life, Functioning, and Depressive Symptom Severity.

Background: The presence of Major Depressive Disorder (MDD) is often comorbid in patients with a variety of general medical conditions (GMCs) which could lead to less favorable outcomes. Objective: The goal of this analysis is to examine functional outcomes of QOL and functioning before and after antidepressant treatment among patients with MDD with and without GMCs. Methods: We performed a secondary analysis based on the STAR*D database. The analysis included two patient groups from the STAR*D trial: 1,198 patients comorbid with MDD and GMCs (MDD + GMC) and 1,082 patients with MDD and no GMCs (MDDnoGMC), as defined by the Cumulative Illness Rating Scale. We analyzed depressive symptom severity, functioning and quality of life (QOL) before and after level 1 treatment with citalopram. Results: At baseline, the MDD + GMC group had significantly lower QOL (p < 0.001) and functioning (p = 0.001) than the MDDnoGMC group, although depressive symptom severity was not significantly different. Following antidepressant treatment, QOL, functioning and depressive symptom severity significantly improved for both MDD + GMC and MDDnoGMC groups. However, patients with MDD + GMC were more likely to experience severe impairments in QOL in (56.8% vs. 43.5% for MDDnoGMC, p < 0.001) and functioning (42.5% vs. 29.3% for MDDnoGMC, p < 0.001) following treatment. The remission rate was significantly lower for MDD + GMC (30.6% vs. 41.1% for MDDnoGMC, p < 0.001). Conclusions: Our findings suggest that antidepressant treatment had a positive impact on patients with and without GMCs. However, those with GMCs experienced not only a lower remission rate, but also continued to experience more significantly severe impairments in QOL and functioning.

Quality of life and functioning of Hispanic patients with Major Depressive Disorder before and after treatment.

BACKGROUND: Similar rates of remission from Major Depressive Disorder (MDD) have been documented between ethnic groups in response to antidepressant treatment. However, ethnic differences in functional outcomes, including patient-reported quality of life (QOL) and functioning, have not been well-characterized. We compared symptomatic and functional outcomes of antidepressant treatment in Hispanic and non-Hispanic patients with MDD. METHODS: We analyzed 2280 nonpsychotic treatment-seeking adults with MDD who received citalopram monotherapy in Level 1 of the Sequenced Treatment Alternatives to Relieve Depression study. All subjects (239 Hispanic, 2041 non-Hispanic) completed QOL, functioning, and depressive symptom severity measures at entry and exit. RESULTS: Hispanic participants had significantly worse QOL scores at entry and exit (p < 0.01). However, after controlling for baseline QOL, there was no difference between Hispanic and non-Hispanic patients' QOL at exit (p = 0.21). There were no significant between-group differences at entry or at exit for depressive symptom severity or functioning. Both groups had significant improvements in depressive symptom severity, QOL, and functioning from entry to exit (all p values < 0.01). Patients with private insurance had lower depressive symptom severity, greater QOL, and better functioning at exit compared to patients without private insurance. LIMITATIONS: This study was a retrospective data analysis, and the Hispanic group was relatively small compared to the non-Hispanic group. CONCLUSIONS: Hispanic and non-Hispanic participants with MDD had similar responses to antidepressant treatment as measured by depressive symptom severity scores, quality of life, and functioning. Nevertheless, Hispanic patients reported significantly worse quality of life at entry.

Quality of Life, Functioning, and Depressive Symptom Severity in Older Adults With Major Depressive Disorder Treated With Citalopram in the STAR*D Study.

OBJECTIVE: Major depressive disorder (MDD) can substantially worsen patient-reported quality of life (QOL) and functioning. Prior studies have examined the role of age in MDD by comparing depressive symptom severity or remission rates between younger and older adults. This study examines these outcomes before and after SSRI treatment. On the basis of prior research, we hypothesized that older adults would have worse treatment outcomes in QOL, functioning, and depressive symptom severity and that nonremitters would have worse outcomes. METHODS: A retrospective secondary data analysis was conducted from the National Institute of Mental Health-funded Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study (July 2001-September 2006). We analyzed data for 2,280 nonpsychotic adults with DSM-IV-TR-defined MDD who received citalopram monotherapy. Older adults were classified as adults aged 65 years and above. All subjects completed patient-reported QOL, functioning, and depressive symptom severity measures at entry and exit. Subjects included 106 older adults and 2,174 adults < 65. MDD remission status posttreatment was also determined. RESULTS: Both older adults and adults < 65 experienced significant improvements and medium to large treatment responses across QOL, functioning, and depressive symptom severity (P < .001). Older adults had smaller treatment effect sizes for all outcomes, particularly functioning. Conversely, mean change scores from entry to exit were equivalent across all outcomes. Remitters at exit had significantly better responses to treatment than nonremitters for the majority of outcomes. CONCLUSION: Findings suggest that older adults and younger adults have comparable treatment responses to citalopram monotherapy, with significant improvements in patient-reported depressive symptom severity, functioning, and QOL. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00021528.

Major Depressive Disorder in Patients With Doctoral Degrees: Patient-reported Depressive Symptom Severity, Functioning, and Quality of Life Before and After Initial Treatment in the STAR*D Study.

OBJECTIVE: This study examined patients with medical or doctoral degrees diagnosed with major depressive disorder (MDD) by analyzing patient-reported depressive symptom severity, functioning, and quality of life (QOL) before and after treatment of MDD. METHODS: Analyses were conducted in a sample of 2280 adult outpatient participants with MDD from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study with complete entry and exit scores for the level 1 (citalopram monotherapy) trial. The sample contained 62 participants who had completed medical or doctoral degrees (DOCS) and 2218 participants without medical or doctoral degrees (non-DOCS). QOL was assessed with the Quality of Life Enjoyment and Satisfaction Questionnaire, functioning was assessed with the Work and Social Adjustment Scale, and depressive symptom severity was assessed with the Quick Inventory of Depressive Symptomatology-Self Report. RESULTS: Both groups (DOCS and non-DOCS) had significant improvement in depressive symptom severity, functioning, and QOL following treatment (with equivalent improvements in mean change values). However, the DOCS group demonstrated larger effect sizes in symptom reduction for depression, increase in functioning, and improvement in QOL compared with the non-DOCS group. Participants who achieved remission from MDD at exit showed significantly greater improvement than nonremitters on functioning and QOL. CONCLUSIONS: Findings from this study indicated that, following citalopram monotherapy, the participants in the DOCS group achieved greater reductions in depressive symptom severity (based on effect sizes) than the participants in the non-DOCS group. For both treatment groups, the findings also showed the positive effect that remission status from MDD can have on QOL and functioning.

Patient-Reported Outcomes of Quality of Life, Functioning, and GI/Psychiatric Symptom Severity in Patients with Inflammatory Bowel Disease (IBD).

BACKGROUND: Patients with inflammatory bowel disease (IBD) are at risk for psychiatric disorders that impact symptom experience and health-related quality of life (HRQOL). Therefore, comprehensive biopsychosocial assessments should be considered in ambulatory care settings. Patient-Reported Outcomes Measurement Information System (PROMIS) measures created by the National Institutes of Health have shown construct validity in a large IBD internet-based cohort, but their validity in ambulatory settings has not been examined. We sought to validate PROMIS patient-reported measures of HRQOL, functioning, and psychiatric symptom severity at a tertiary IBD clinic. METHODS: Adult patients (n = 110) completed the PROMIS Global Health scale, PROMIS-29, SF-12, and WHODAS 2.0. Pearson's correlation coefficients (r) determined the relationships between scores to validate the PROMIS Global Health Physical and Mental metrics, compared with the SF-12 and WHODAS 2.0. We compared these measures by disease subtype of Crohn's disease or ulcerative colitis. RESULTS: PROMIS measures were highly correlated (r range = 0.64-0.82) with standard measures of HRQOL and functioning. On the PROMIS Global Health measures, 20.9% had impaired physical health, and 13.7% had impaired mental health. Impairments were reported in pain interference (20% of patients), anxiety (18.2%), satisfaction with social role (15.5%), physical functioning (10.9%), fatigue (10%), depression (7.3%), and sleep disturbance (5.5%). Patients with Crohn's disease had worse scores than those with ulcerative colitis on measures of the global physical health (P = 0.027), physical functioning (P = 0.047), and pain interference (P = 0.0009). CONCLUSIONS: PROMIS instruments provide valid assessment of HRQOL and functioning in ambulatory adults with IBD. Of note, patients with Crohn's disease demonstrated significantly worse impairments than those with ulcerative colitis.

Quality of Life and Functioning in Comorbid Posttraumatic Stress Disorder and Major Depressive Disorder After Treatment With Citalopram Monotherapy.

OBJECTIVES: Posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) often have high comorbidity, consequently influencing patient-reported outcomes of depressive symptom severity, quality of life (QOL), and functioning. We hypothesized that the combined effects of concurrent PTSD and MDD would result in worse treatment outcomes, whereas individuals who achieved MDD remission would have better treatment outcomes. METHODS: We analyzed 2280 adult participants who received level 1 treatment (citalopram monotherapy) in the Sequenced Treatment Alternatives to Relieve Depression study, including 2158 participants with MDD without comorbid PTSD and 122 participants with MDD with comorbid PTSD (MDD + PTSD). Post hoc analysis examined the proportion of participants whose scores were within normal or severely impaired for functioning and QOL. Remission status at exit from MDD was also determined. RESULTS: At entry, participants with MDD + PTSD experienced significantly worse QOL, functioning, and depressive symptom severity compared with participants with MDD without comorbid PTSD. Although both groups had significant improvements in functioning and QOL posttreatment, the participants with MDD + PTSD were less likely to achieve remission from MDD. CONCLUSIONS: Findings suggested that participants with MDD + PTSD are at a greater risk for severe impairment across all domains and less likely to achieve remission from MDD after treatment with citalopram monotherapy. As such, the use of patient-reported measures of QOL and functioning may inform practicing clinicians' and clinical trial researchers' abilities to develop appropriate interventions and monitor treatment efficacy. More importantly, we encourage clinicians and health care providers to routinely screen for PTSD in patients with MDD because this at-risk group requires tailored and specific pharmacotherapy and psychotherapy interventions beyond traditionally standard treatments for depression.

Diagnostic utility of the HIV dementia scale and the international HIV dementia scale in screening for HIV-associated neurocognitive disorders among Spanish-speaking adults.

Given that neurocognitive impairment is a frequent complication of HIV-1 infection in Spanish-speaking adults, the limited number of studies assessing HIV-associated neurocognitive disorders (HAND) in this population raises serious clinical concern. In addition to being appropriately translated, instruments need to be modified, normed, and validated accordingly. The purpose of the current study was to examine the diagnostic utility of the HIV Dementia Scale (HDS) and International HIV Dementia Scale (IHDS) to screen for HAND in Spanish-speaking adults living with HIV infection. Participants were classified as either HAND (N = 47) or No-HAND (N = 53) after completing a comprehensive neuropsychological evaluation. Receiver operating characteristic analyses found the HDS (AUC = .706) was more sensitive to detecting HAND than the IHDS (AUC = .600). Optimal cutoff scores were 9.5 for the HDS (PPV = 65.2%, NPV = 71.4%) and 9.0 for the IHDS (PPV = 59.4%, NPV = 59.1%). Canonical Correlation Analysis found the HDS converged with attention and executive functioning. Findings suggest that while the IHDS may not be an appropriate screening instrument with this population, the HDS retains sufficient statistical validity and clinical utility to screen for HAND in Spanish-speaking adults as a time-efficient and cost-effective measure in clinical settings with limited resources.

Trazodone for Insomnia: A Systematic Review.

OBJECTIVE: While trazodone is approved for the treatment of depression, the off-label use of this medication for insomnia has surpassed its usage as an antidepressant. In this systematic review, we examined the evidence for the efficacy and safety of trazodone for insomnia. METHODS: A literature search was conducted using MEDLINE/PubMed databases from the past 33 years (1983-2016) and the keywords insomnia, trazodone, sedative, treatment, and hypnotics. The results were restricted to English language and human subjects. All randomized clinical trials, meta-analyses, observational studies, and placebo-controlled trials regarding trazodone for the treatment of primary or secondary insomnia were reported, per PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The study selection process yielded a total of 45 studies. RESULTS: Evidence for the efficacy of trazodone has been repeatedly demonstrated for primary insomnia, as well as secondary insomnia, including for symptoms that are a result of depression, dementia, and being a healthy man. Earlier studies (1980-2000) focused on utilizing trazodone at high doses (≥100mg/d) for the treatment of insomnia among the depressed population; however, since the 2000s, the utility of trazodone has been expanded to treat secondary insomnia among the non-depressed population as well. The side effects are dose-dependent, and the most common is drowsiness. CONCLUSION: A review of the literature suggests that there are adequate data supporting the efficacy and general safety of the low-dose use of trazodone for the treatment of insomnia.

Discrepancies between bilinguals' performance on the Spanish and English versions of the WAIS Digit Span task: Cross-cultural implications.

This study explored within-subjects differences in the performance of 40 bilingual participants on the English and Spanish versions of the Wechsler Adult Intelligence Scale (WAIS) Digit Span task. To test the linguistic hypothesis that individuals would perform worse in Spanish because of its syllabic demand, we compared the number of syllables correctly recalled by each participant for every correct trial. Our analysis of the correct number of syllables remembered per trial showed that participants performed significantly better (i.e., recalling more syllables) in Spanish than in English on the total score. Findings suggest the Spanish version of the Digit Span (total score) was significantly more difficult than the English version utilizing traditional scoring methods. Moreover, the Forward Trial, rather than the Backward Trial, was more likely to show group differences between both language versions. Additionally, the Spanish trials of the Digit Span were correlated with language comprehension and verbal episodic memory measures, whereas the English trials of the Digit Span were correlated with confrontational naming and verbal fluency tasks. The results suggest that more research is necessary to further investigate other cognitive factors, rather than just syllabic demand, that might contribute to performance and outcome differences on the WAIS Digit Span in Spanish-English bilinguals.