-
Der Nervenarzt Jun 2024In addition to trauma-focussed psychotherapy, pharmacological treatment is often unavoidable, especially in patients with severe posttraumatic stress disorder (PTSD). As... (Review)
Review
In addition to trauma-focussed psychotherapy, pharmacological treatment is often unavoidable, especially in patients with severe posttraumatic stress disorder (PTSD). As long as comorbid disorders do not dictate the pharmacotherapy approach, sertraline and paroxetine, along with other off-label prescribable substances approved in Germany, can be used for the treatment of PTSD. Venlafaxine, in particular, has shown good effectiveness in studies, whereas risperidone has shown lower effectiveness in augmentation. Overall, only a small to medium effect size is to be expected for all substances. Psychopharmacotherapy plays an important role in addressing sleep disorders, which are highly prevalent in PTSD. Treatment of trauma-related nightmares can be attempted with doxazosin or clonidine. In contrast, there are limited empirical data available for sleep disorders associated with PTSD, but the pharmacological treatment of insomnia can provide some guidance.
PubMed: 38916664
DOI: 10.1007/s00115-024-01684-8 -
Biochemical and Biophysical Research... Jun 2024To explore the feasibility of screening potential drugs for the treatment of diabetic kidney disease (DKD) using a single-cell transcriptome sequencing dataset and...
OBJECTIVE
To explore the feasibility of screening potential drugs for the treatment of diabetic kidney disease (DKD) using a single-cell transcriptome sequencing dataset and Connectivity Map (CMap) database screening.
METHODS
A DKD single-nucleus transcriptome sequencing dataset was analyzed using Seurat 4.0 to obtain specific podocyte subclusters and differentially expressed genes (DEGs) related to DKD. These DEGs were subsequently subjected to a search against the CMap database to screen for drug candidates. Cell and animal experiments were conducted to evaluate the efficacy of the top 3 drug candidates.
RESULTS
Initially, we analyzed the DKD single-nucleus transcriptome sequencing dataset to obtain intrinsic renal cells such as podocytes, endothelial cells, mesangial cells, proximal tubular cells, collecting duct cells and immune cells. Podocytes were further divided into four subclusters, among which the proportion of POD_1 podcytes was significantly greater in DKD kidneys than in control kidneys (34.0 % vs. 3.4 %). The CMap database was searched using the identified DEGs in the POD_1 subcluster, and the drugs, including tozasertib, paroxetine, and xylazine, were obtained. Cell-based experiments showed that tozasertib, paroxetine and xylazine had no significant podocyte toxicity in the concentration range of 0.01-50 μM. Tozasertib, paroxetine, and xylazine all reversed the advanced glycation end products (AGEs)-induced decrease in podocyte marker levels, but the effect of paroxetine was more prominent. Animal experiments showed that paroxetine decreased urine ALB/Cr levels in DKD model mice by approximately 51.5 % (115.7 mg/g vs. 238.8 mg/g, P < 0.05). Histopathological assessment revealed that paroxetine attenuated basement membrane thickening, restored the number of foot processes of podocytes, and reduced foot process fusion. In addition, paroxetine also attenuated renal tubular-interstitial fibrosis. Mechanistically, paroxetine inhibited the expression of GRK2 and NLRP3, decreased the phosphorylation level of p65, restored NRF2 expression, and relieved inflammation and oxidative stress.
CONCLUSION
This strategy based on single-cell transcriptome sequencing and CMap data can facilitate the identification and aid the rapid development of clinical DKD drugs. Paroxetine, screened by this strategy, has excellent renoprotective effects.
PubMed: 38905995
DOI: 10.1016/j.bbrc.2024.150263 -
The Primary Care Companion For CNS... Jun 2024To review the literature on the neurobiological mechanisms of obsessive-compulsive symptoms (OCS) in people with dementia. MEDLINE/PubMed, CENTRAL, and PsycNet... (Review)
Review
To review the literature on the neurobiological mechanisms of obsessive-compulsive symptoms (OCS) in people with dementia. MEDLINE/PubMed, CENTRAL, and PsycNet databases were searched from inception to March 2023. Original studies of any methodology with newly published data on the neurobiological underpinnings of OCS in patients with dementia, regardless of patient age or comorbidity and publication year, were included. The following search terms were used: (Obses* OR compul* OR OCD) AND (cognitive de* OR cognitive dysfunction OR cognitive disfunction OR dementia). Individual study data were extracted onto a piloted extractions sheet. Patients with dementia and OCS were reported to have atrophy and hypoperfusion of frontal, temporal, striatal, and limbic structures. Serotonergic agents may be efficacious in reducing OCS. One randomized controlled trial of paroxetine in behavioral symptoms of dementia did not show efficacy. Evidence of dopaminergic dysfunction is too sparse to draw conclusions. Microglia dysfunction mediates obsessive-compulsive-like symptoms. Mutations of microtubule-associated protein τ may increase the risk of OCS. Cognitive self-consciousness and obsessive-compulsive-related cognitions may mediate OCS in old age. Dysfunction of the processing of one class of stimuli may increase the salience of other classes of stimuli, leading to OCS. Frontal lobe hypometabolism and temporal lobe atrophy and hypometabolism are unexpected given previous research in obsessive compulsive disorder. Serotonergic agents have encouraging efficacy in case reports but require more specific research. .
Topics: Humans; Obsessive-Compulsive Disorder; Dementia
PubMed: 38905511
DOI: 10.4088/PCC.23r03689 -
MDM Policy & Practice 2024Global climate change is resulting in dramatic increases in wildfires. Individuals exposed to wildfires experience a high burden of posttraumatic stress disorder...
UNLABELLED
Global climate change is resulting in dramatic increases in wildfires. Individuals exposed to wildfires experience a high burden of posttraumatic stress disorder (PTSD), and the cost-effectiveness of the treatment options to address PTSD from wildfires has not been studied. The objective of this study was to conduct a cost-utility analysis comparing screening followed by treatment with paroxetine or trauma-focused cognitive behavioral therapy (TF-CBT) versus no screening in Canadian adult wildfire evacuees. Using a Markov model, quality-adjusted life-years (QALYs) and costs were evaluated over a 5-y time horizon using health care and societal perspectives. All costs and utilities in the model were discounted at 1.5%. Probabilistic and deterministic sensitivity analyses examined the uncertainty in the incremental net monetary benefit (INMB) under a willingness-to-pay threshold of $50,000. From a societal perspective, no screening (NMB = $177,641) was dominated by screening followed by treatment with paroxetine (NMB = $180,733) and TF-CBT (NMB = $181,787), with TF-CBT having the highest likelihood of being cost-effective at a willingness-to-pay threshold of $50,000 per QALY (probability = 0.649). The initial prevalence of PTSD, probability of acceptance of treatment, and costs of productivity had the largest impact on the INMB of both paroxetine or TF-CBT versus no screening. Neither intervention was cost-effective at a willingness-to-pay threshold of $50,000 per QALY from a health care perspective. Screening followed by treatment with paroxetine or TF-CBT compared with no screening was found to be cost-saving while providing additional QALYs in wildfire evacuees. Governments should consider funding screening programs for PTSD followed by treatment with TF-CBT for wildfire evacuees.
HIGHLIGHTS
Two prior studies examined the cost-effectiveness of screening followed by treatment for PTSD among individuals exposed to other disaster-type events (i.e., terrorist attack and Hurricane Sandy) and found screening followed by treatment (i.e., cognitive behavioral therapy [CBT]) to be highly cost-effective.Among wildfire evacuees, screening followed by treatment with paroxetine or trauma-focused (TF)-CBT provides additional quality-adjusted life-years (QALYs) and is cost-saving from a societal perspective. TF-CBT was the treatment option found most likely to be cost-effective.Neither treatment option was cost-effective at a willingness-to-pay threshold of $50,000 per QALY from a health care perspective.Screening programs for PTSD should be considered for wildfire evacuees, and individuals diagnosed with PTSD could be prescribed either TF-CBT or paroxetine depending on their preference and resources availability.
PubMed: 38904072
DOI: 10.1177/23814683241260423 -
Diabetes, Obesity & Metabolism Jun 2024To investigate the effects of the selective serotonin reuptake inhibitors (SSRIs) sertraline and paroxetine at therapeutically relevant concentrations on beta-cell mass...
AIMS
To investigate the effects of the selective serotonin reuptake inhibitors (SSRIs) sertraline and paroxetine at therapeutically relevant concentrations on beta-cell mass and function.
METHODS
Viability was quantified in mouse insulinoma (MIN6) beta cells and mouse islets after 48-h exposure to sertraline (1-10 μM) or paroxetine (0.01-1 μM) using the Trypan blue exclusion test. The effects of therapeutic concentrations of these SSRIs on insulin secretion were determined by static incubation and perifusion experiments, while islet apoptosis was investigated by Caspase-Glo 3/7 assay, TUNEL staining and quantitative PCR analysis. Finally, proliferation of MIN6 and mouse islet beta cells was assessed by bromodeoxyuridine (BrdU) enzyme-linked immunosorbent assay and immunofluorescence.
RESULTS
Sertraline (0.1-1 μM) and paroxetine (0.01-0.1 μM) were well tolerated by MIN6 beta cells and islets, whereas 10 μM sertraline and 1 μM paroxetine were cytotoxic. Exposure to 1 μM sertraline and 0.1 μM paroxetine significantly potentiated glucose-stimulated insulin secretion from mouse and human islets. Moreover, they showed protective effects against cytokine- and palmitate-induced apoptosis of islets, they downregulated cytokine-induced Stat1 and Traf1 mRNA expression, and they significantly increased proliferation of mouse beta cells.
CONCLUSIONS
Our data demonstrate that sertraline and paroxetine act directly on beta cells to enhance glucose-stimulated insulin secretion and stimulate beta-cell mass expansion by increasing proliferation and decreasing apoptosis. These drugs are therefore likely to be appropriate for treating depression in people with type 2 diabetes.
PubMed: 38888050
DOI: 10.1111/dom.15701 -
Pharmacogenomics May 2024We herein inferred the genetic diversity of CYP450 isoenzymes to predict the percentage of patients who need dose adjustment in drugs used in psychiatry. Data of 784...
We herein inferred the genetic diversity of CYP450 isoenzymes to predict the percentage of patients who need dose adjustment in drugs used in psychiatry. Data of 784 Greek patients receiving psychiatric care who were genotyped for CYP2D6, CYP2C19, CYP1A2, CYP3A5 and CYP2C9 isoenzymes were inferred to gene-drug pairs according to the US FDA, Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group annotations and published literature. Atypical metabolism was found for 36.8% of patients in CYP2D6, 49.2% in CYP2C19, 45% in CYP1A2, 16.7% in CYP3A5 and 41.8% in CYP2C9. Dosage adjustment need was estimated for 10.2% of venlafaxine, 10.0% of paroxetine, 6.4% of sertraline, 30.8% of citalopram, 52.1% of escitalopram, 18.2% of fluvoxamine, 54.1% of tricyclic antidepressants, 16.7% of zuclopenthixol, 10.6% of haloperidol and 13.3% of risperidone treated patients. Clinical psychiatric pharmacogenomic implementation holds promise to improve drug effectiveness and safety.
PubMed: 38884939
DOI: 10.1080/14622416.2024.2346072 -
Chinese Medical Journal Jun 2024G protein-coupled receptor kinase 2 (GRK2) could participate in the regulation of diverse cells via interacting with non-G-protein-coupled receptors. In the present...
BACKGROUND
G protein-coupled receptor kinase 2 (GRK2) could participate in the regulation of diverse cells via interacting with non-G-protein-coupled receptors. In the present work, we explored how paroxetine, a GRK2 inhibitor, modulates the differentiation and activation of immune cells in rheumatoid arthritis (RA).
METHODS
The blood samples of healthy individuals and RA patients were collected between July 2021 and March 2022 from the First Affiliated Hospital of Anhui Medical University. C57BL/6 mice were used to induce the collagen-induced arthritis (CIA) model. Flow cytometry analysis was used to characterize the differentiation and function of dendritic cells (DCs)/T cells. Co-immunoprecipitation was used to explore the specific molecular mechanism.
RESULTS
In patients with RA, high expression of GRK2 in peripheral blood lymphocytes, accompanied by the increases of phosphatidylinositol 3 kinase (PI3K), protein kinase B (AKT), and mammalian target of rapamycin (mTOR). In animal model, a decrease in regulatory T cells (Tregs), an increase in the cluster of differentiation 8 positive (CD8+) T cells, and maturation of DCs were observed. Paroxetine, when used in vitro and in CIA mice, restrained the maturation of DCs and the differentiation of CD8+ T cells, and induced the proportion of Tregs. Paroxetine inhibited the secretion of pro-inflammatory cytokines, the expression of C-C motif chemokine receptor 7 in DCs and T cells. Simultaneously, paroxetine upregulated the expression of programmed death ligand 1, and anti-inflammatory cytokines. Additionally, paroxetine inhibited the PI3K-AKT-mTOR metabolic pathway in both DCs and T cells. This was associated with a reduction in mitochondrial membrane potential and changes in the utilization of glucose and lipids, particularly in DCs. Paroxetine reversed PI3K-AKT pathway activation induced by 740 Y-P (a PI3K agonist) through inhibiting the interaction between GRK2 and PI3K in DCs and T cells.
CONCLUSION
Paroxetine exerts an immunosuppressive effect by targeting GRK2, which subsequently inhibits the metabolism-related PI3K-AKT-mTOR pathway of DCs and T cell in RA.
PubMed: 38879805
DOI: 10.1097/CM9.0000000000003165 -
Fundamental & Clinical Pharmacology Jun 2024Pharmacologic management of mental health illnesses in patients receiving dialysis is complex and lacking data. (Review)
Review
BACKGROUND
Pharmacologic management of mental health illnesses in patients receiving dialysis is complex and lacking data.
OBJECTIVE
Our objective was to synthesize published data for the treatment of depression, bipolar and related disorders, schizophrenia or psychotic disorders, and anxiety disorders in adults receiving hemodialysis or peritoneal dialysis.
METHODS
We undertook a scoping review, searching the following databases: Medline, Embase, CINAHL, PsycINFO, Cochrane Library, Scopus, and Web of Science. Data on patients who received only short-term dialysis, a kidney transplant, or non-pharmacologic treatments were excluded.
RESULTS
Seventy-three articles were included: 41 focused on depression, 16 on bipolar disorder, 13 on schizophrenia and psychotic disorders, 1 on anxiety disorders, and 2 addressing multiple mental health illnesses. The majority of depression studies reported on selective serotonin reuptake inhibitors (SSRIs) as a treatment. Sertraline had the most supporting data with use of doses from 25 to 200 mg daily. Among the remaining SSRIs, escitalopram, citalopram, and fluoxetine were studied in controlled trials, whereas paroxetine and fluvoxamine were described in smaller reports and observational trials. There are limited published data on other classes of antidepressants and on pharmacological management of anxiety. Data on treatment for patients with bipolar disorder or schizophrenia and related disorders are limited to case reports.
CONCLUSION
Over half of the studies included were case reports, thus limiting conclusions. More robust data are required to establish effect sizes of pharmacological treatments prior to providing specific recommendations for their use in treating mental health illnesses in patients receiving dialysis.
PubMed: 38877814
DOI: 10.1111/fcp.13022 -
International Clinical... Jun 2024Currently, there are few pharmacotherapy options for clinicians treating post-traumatic stress disorder (PTSD), and antidepressants are usually the medication of choice....
Currently, there are few pharmacotherapy options for clinicians treating post-traumatic stress disorder (PTSD), and antidepressants are usually the medication of choice. This meta-analysis aimed to review the efficacy of antidepressants in the acute treatment of PTSD in adults while investigating the contribution of study design and placebo response to the findings of these studies. Randomized, double-blind, placebo-controlled clinical trials that compared antidepressants with placebo for acute treatment of PTSD were selected. Standardized mean difference (SMD) in change in Clinician-Administered PTSD Scale scores were pooled after examining for heterogeneity. A random-effects meta-analysis was performed. Twenty-nine antidepressant-placebo comparisons, involving 4575 subjects, were analyzed. The SMD among all studies was 0.25, a small to medium effect size, lower than that in studies of antidepressants in adult major depressive disorder. The SMDs for low and high mean placebo responses, were 0.27 and 0.22, respectively. The overall SMD for paroxetine studies was in the moderate range (0.43) and that for sertraline studies was in the small range (0.12). Our findings suggest that antidepressants have modest efficacy in alleviating PTSD symptoms. Patient-level meta-analyses are required to further explore the potential clinical relevance of sertraline for PTSD.
PubMed: 38869978
DOI: 10.1097/YIC.0000000000000554