Phosphodiesterase inhibitor and selective serotonin reuptake inhibitor combination therapy versus monotherapy for the treatment of major depressive disorder: a systematic review and meta-analysis.

Selective serotonin reuptakeinhibitors (SSRIs) are the gold standard treatment for major depressive disorder (MDD). However, the use of phosphodiesterase (PDE) inhibitors in the treatment of MDD remains unclear. Our study aims to compare the effect of PDE inhibitor combination therapy to SSRI monotherapy for the treatment of MDD. We performed a comprehensive literature search using PubMed, EMBASE, and Web of Science databases, for studies that assess the impact of PDE inhibitor therapy on MDD patients. The primary outcome of our study was treatment response rate at the end of study time. Pooled odds ratio (OR) and corresponding 95% confidence intervals (CIs) were calculated using the random-effects model. A P -value <0.05 was considered statistically significant. A total of four randomized control trials (RCTs), including 270 patients with MDD, were included in the analysis. Follow-up periods ranged from 6 to 12 weeks. The PDE inhibitor group was associated with a significantly higher treatment response rate (OR, 4.77; 95% CI, 2.05-11.12; P = 0.0003). Our meta-analysis demonstrated that MDD patients receiving PDE inhibitor combination therapy had a higher treatment response rate than MDD patients receiving SSRI monotherapy. Further large-scale RCTs with long-term follow-ups are necessary to validate our findings.

Considerations for fair prioritization of COVID-19 vaccine and its mandate among healthcare personnel.

With current COVID-19 vaccine demand outweighing supply and the emergency authorization/rollout of three novel vaccines in the United States, discussions continue regarding fair prioritization among various groups for this scarce resource. The US federal government's recommended vaccination schedule, meant to assist states with vaccine allocation, demonstrates fair ethical considerations; however, difficulties remain comparing various groups to determine fair vaccine access and distribution. Although strides have been taken to analyze risks versus benefits of early vaccination across certain high-risk populations, prioritizing vulnerable populations versus essential workers remains challenging for multiple reasons. Similarly, as COVID-19 vaccine allocation and distribution continues in the US and in other countries, topics that require continued consideration include sub-prioritization among currently prioritized groups, prioritization among vulnerable groups disproportionately affected by the COVID-19 pandemic, like ethnic minorities, and holistic comparisons between groups who might receive various and disparate benefits from vaccination. Although all current COVID-19 vaccines are emergency authorization use only and a vaccine mandate would be considered only once these vaccines are licensed by the US Food and Drug Administration, future vaccination policies require time and deliberation. Similarly, given current vaccine hesitancy, mandatory vaccination of certain groups, like healthcare personnel, may need to be considered when these vaccines are licensed, especially if voluntary vaccination proves insufficient. Continued discussions regarding risks versus benefits of mandatory COVID-19 vaccination and the unique role of healthcare personnel in providing a safe healthcare environment could lead to better deliberation regarding potential policies. This commentary aims to address both questions of fair prioritization and sub-prioritization of various groups, as well as ethical considerations for mandatory COVID-19 vaccination among healthcare personnel.

Dispositional optimism mediates relations between childhood maltreatment and PTSD symptom severity among trauma-exposed adults.

BACKGROUND: Experiences of maltreatment in childhood, such as abuse and neglect, have been associated with poorer psychological well-being in adulthood, including elevated risk of revictimization and increased likelihood of developing posttraumatic stress disorder (PTSD) symptoms. Maltreatment has also been associated with reduced resources related to resilience, such as optimism, which may act as a protective factor for mental health. OBJECTIVES: In this study, we examined the mediating role of dispositional optimism in the relationship between childhood maltreatment and PTSD symptom severity from recent trauma in a sample of adults (n = 108) who presented to their local emergency department following trauma. METHODS: We analyzed six models to account for cumulative childhood maltreatment as well as five primary subtypes of maltreatment: emotional abuse, physical abuse, sexual abuse, emotional neglect, and physical neglect. RESULTS: Greater dispositional optimism mediated relations between total maltreatment and decreased PTSD severity (Bab = .056, SE = .029, 95 % CI [.009, .121]). Optimism also mediated relations between all maltreatment subtypes and PTSD severity, except sexual abuse. CONCLUSIONS: These results may suggest optimism and positive psychology interventions as effective techniques in reducing the likelihood of PTSD development and severity in trauma-exposed individuals.

Valproate-Induced Hyperammonemic Encephalopathy in General Hospital Patients With One or More Psychiatric Disorders.

BACKGROUND: Divalproex sodium/valproic acid (VPA) is an antiepileptic drug approved for use in epilepsy and bipolar disorder. Valproate-induced hyperammonemia occurs in up to 50% of VPA-treated patients, some of whom may become encephalopathic. Valproate-induced hyperammonemic encephalopathy (VHE) is thought to be rare, and for a variety of reasons, the diagnosis requires a high index of suspicion. OBJECTIVE: The study's goals are to determine how common VHE is, and the quality of treatment provided when diagnosed. METHODS: Retrospective, cross-sectional survey of general hospital patients. The hospital's laboratory and pharmacy databases were combined to identify a cohort of all VPA-treated patients who developed hyperammonemia during a 5-year period. Hospital records of the subset of patients with a psychiatric disorder were selected and reviewed for data collection. RESULTS: Twenty of 793 (2.52%) VPA-treated patients had signs and symptoms consistent with VHE. The majority were White males on multiple psychotropic agents. Valproate was appropriately discontinued in 8 (40%) patients. Lactulose was the only ammonia-lowering drug used, and it was administered to 6 patients and only one among them had VPA discontinued. CONCLUSION: Study results indicate that VHE may be more common in psychiatric patients than previously assumed but underrecognized and inadequately treated. The diagnosis of VHE requires a high index of suspicion. Outcome is favorable once it is recognized and treated appropriately.

Valproate-induced hyperammonemic encephalopathy: a brief review.

BACKGROUND: This brief review presents a comprehensive evaluation of valproate-induced encephalopathy (VHE) and also discusses potential mechanisms of the condition. SCOPE: Sodium valproate (VPA) is an effective antiepileptic drug used in neurology as well as in psychiatry, in adults and children. VHE requires early diagnosis and management. Focused research efforts in understanding the condition will help decrease its incidence. Delay in recognition of VHE can result in the development of potentially life-threatening complications. FINDINGS: Management options are described. Since VPA frequently causes a modest rise in plasma ammonia levels which is asymptomatic, it is important to recognize the symptoms of VHE promptly and to correlate them with the plasma ammonia levels. CONCLUSIONS: Although there are several case reports on VHE, this review is a comprehensive evaluation of its causes and potential mechanisms. Rapid diagnosis and management will help in reducing VHE-related morbidity.

Testosterone enhances dopamine depletion by methamphetamine in male, but not female, mice.

We examined the effects of varying concentrations of testosterone propionate (T) treatment within intact and gonadectomized male and female mice with regard to its capacity to alter striatal dopamine (DA) depletion in response to a neurotoxic regimen of methamphetamine (MA). Administration of T at 24h prior to MA significantly increased striatal DA depletion in intact and gonadectomized male mice. Similar treatments administered to intact and gonadectomized female mice failed to alter striatal DA concentrations in response to MA. These results demonstrate that T can enhance MA-induced neurotoxicity in male, but not in female, mice. Such findings have important implications with regard to sex differences in nigrostriatal dopaminergic function, in general, and, in specific, to sex differences related to nigrostriatal dopaminergic neurotoxicity and neurodegeneration like that in response to MA and in Parkinson's disease, where a greater incidence is typically reported for males.

Arginase blockade lessens endothelial dysfunction after thrombosis.

INTRODUCTION: Acute arterial thrombosis causes endothelial dysfunction due to decreased nitric oxide bioactivity. Increased arginase activity may modulate intracellular L-arginine levels, the substrate for nitric oxide. The purpose of this study was to identify the role of arginase in endothelial dysfunction in cell culture and in the vasomotor response of arteries exposed to thrombus. METHODS: Rat aortic endothelial cells were exposed to thrombin at different time points. The cell extract was analyzed by immunoblotting and real-time polymerase chain reaction. Adult male rats underwent infrarenal aortic thrombosis by clip ligature for 1 hour. Infrarenal aortic ring segments were harvested and placed in physiologic buffer baths, and a force transducer was used to measure endothelial-dependent relaxation (EDR) and endothelial-independent relaxation (EIR). Arginase blockade was performed by incubating infrarenal aortic ring segments with arginase inhibitors for 1 hour before measuring EDR. Whole tissue extracts also underwent immunoblot analysis. The EDR and EIR curves were compared with analyses of variance. RESULTS: A 6.76 +/- 1.4-fold induction in arginase I message levels (P = .001) was found in rat aortic endothelial cells exposed to thrombin (30 U/mL), and arginase I protein levels increased 2.1 times. The eight infrarenal aortic ring segments exposed to thrombosis for 1 hour had diminished EDR curves compared with 14 nonthrombosed normal segments (controls). The maximum (+/- SEM) EDR (acetylcholine 10(-5)M dose) in control infrarenal aortic ring segments was 108% +/- 4.3% compared with 63% +/- 6.2% for thrombosed infrarenal aortic ring segments (P < .001). Exposure to arterial thrombosis resulted in a 3.8-times increase in arginase I protein levels in infrarenal aortic ring segments. Preincubation of nine infrarenal aortic ring segments with the nonspecific (difluoromethylornithine) and six with specific ([S]-[2-boronoethyl]-L-Cysteine-HCl [BEC]) arginase inhibitor for 1 hour significantly increased the maximum EDR compared with untreated thrombosed segments (104 +/- 5.2, 108 +/- 7.6 vs 63% +/- 6.2, P < .001). EDR curves for difluoromethylornithine- and BEC-treated infrarenal aortic ring segments were superimposed on control EDR curves. The EIR and the vasoconstriction with norepinephrine for all groups were similar. CONCLUSION: Endothelial cells exposed to thrombin have increased arginase I messenger RNA and protein levels. Arterial thrombosis causes endothelial dysfunction without affecting smooth muscle responsiveness. Arginase blockade can lead to normalization of arterial vasomotor function.

Arginase activity is increased by thrombin: a mechanism for endothelial dysfunction in arterial thrombosis.

BACKGROUND: Earlier observations implicate arterial thrombosis causing endothelial dysfunction by decreasing nitric oxide (NO) levels. NO levels are restored by regional L-arginine supplementation in animal models. The purpose of this study was to investigate the roles of thrombus components in NO generation. STUDY DESIGN: Human umbilical vein endothelial cells were harvested and cultured. The thrombus components thrombin, thrombin receptor agonist peptide (TRAP), and fibrin were added to a media of confluent human umbilical vein endothelial cells. Endothelial nitric oxide synthase (eNOS) activity was assayed by measuring conversion of L-arginine to L-citrulline. Endothelial NOS mRNA levels were quantitated using real-time polymerase chain reaction. Cellular membrane transport of L-arginine through the y+ channel was assayed with (14)C-labeled L-arginine. Arginase activity was determined as the conversion of (14)C L-arginine to (14)C urea and trapped as Na(2)(14)CO(3) for scintillation counting. Arginase protein amounts were assessed using Western blotting. RESULTS: Endothelial cells exposed to thrombin for 4 hours led to increased arginase activity. Thrombin (10 U/mL) caused a 1.6-fold increase compared with that in controls (320+/-29 microM urea/min versus 194+/-10 microM urea/min, p=0.03), and thrombin (30 U/mL) increased arginase activity 2.1-fold (398+/-27 microM urea/min, p < 0.001, versus controls); thrombin at 1 U/mL and fibrin had no effect. TRAP (50 microM) had an effect similar to that of thrombin 10 U/mL (316+/-21 microM urea/min, p < 0.01, versus controls). Protein amounts of arginase corresponded with activity levels. Neither eNOS nor inducible nitric oxide synthase (iNOS) activities were affected by exposure to thrombin and TRAP for 4 hours. Similarly, quantification of eNOS, iNOS, and endothelin-1 mRNA did not change, although CL-100, a known thrombin-inducible gene, was upregulated. Finally, transport of L-arginine into endothelial cells was unaffected by thrombin, TRAP, and fibrin exposure. CONCLUSIONS: Endothelial cells exposed to thrombin have increased arginase enzymatic activity, and the remainder of NO generation capability is unaffected. L-arginine supplementation or arginase blockade may counteract endothelial dysfunction in the setting of acute arterial thrombosis.